BANG
MSS
2004/139
c
BANG
University of California Berkeley
Regional Oral History Office University of California
The Bancroft Library Berkeley, California
Program in the History of the Biological Sciences and Biotechnology
Roberto Crea
DNA CHEMISTRY AT THE DAWN OF COMMERCIAL BIOTECHNOLOGY
Interviews Conducted by
Sally Smith Hughes, Ph.D.
in 2002
Copyright (Q 2004 by The Regents of the University of California
Since 1954 the Regional Oral History Office has been interviewing leading participants in or well-placed
witnesses to major events in the development of northern California, the West, and the nation. Oral history
is a method of collecting historical information through tape-recorded interviews between a narrator with
firsthand knowledge of historically significant events and a well-informed interviewer, with the goal of
preserving substantive additions to the historical record. The tape recording is transcribed, lightly edited
for continuity and clarity, and reviewed by the interviewee. The corrected manuscript is indexed, bound
with photographs and illustrative materials, and placed in The Bancroft Library at the University of
California, Berkeley, and in other research collections for scholarly use. Because it is primary material,
oral history is not intended to present the final, verified, or complete narrative of events. It is a spoken
account, offered by the interviewee in response to questioning, and as such it is reflective, partisan, deeply
involved, and irreplaceable.
All uses of this manuscript are covered by a legal agreement between The
Regents of the University of California and Roberto Crea, dated June 27,
2002. The manuscript is thereby made available for research purposes.
All literary rights in the manuscript, including the right to publish, are
reserved to The Bancroft Library of the University of California,
Berkeley. No part of the manuscript may be quoted for publication
without the written permission of the Director of The Bancroft Library of
the University of California, Berkeley.
Requests for permission to quote for publication should be addressed to
the Regional Oral History Office, The Bancroft Library, Mail Code 6000,
University of California, Berkeley 94720-6000, and should include
identification of the specific passages to be quoted, anticipated use of the
passages, and identification of the user.
It is recommended that this oral history be cited as follows:
Roberto Crea, "DNA Chemistry at the Dawn of
Comercial Biotechnology," an oral history conducted in
2002 by Sally Smith Hughes, Ph.D., Regional Oral
History Office, The Bancroft Library, University of
California, Berkeley, 2004.
Copy no.
Roberto Crea, 2003
photo courtesy of Roberto Crea
TABLE OF CONTENTS Roberto Crea
BIOTECHNOLOGY SERIES HISTORY by Sally Smith Hughes i
BIOTECHNOLOGY SERIES LIST iii
INTERVIEW HISTORY by Sally Smith Hughes v
BIOGRAPHICAL INFORMATION vii
Family Background and Education in Italy 1
Grandparents, mother, and father 1
Early education, interest in science and engineering
Siblings
Commuting to University of Messina
Catholicism 3
Family life 4
Chemistry studies at University of Messina 5
Doctoral studies in biochemistry with Professor Castellani in Pavia
Professor Campagnari s course on DNA replication 9
Campagnari suggests studying abroad and a plan to synthesize DNA substrates 10
Fellowships in DNA Chemistry, University of Leiden, The Netherlands, 1974-1976 10
Drive to Leiden, English language deficiency 1 1
Introduction to Professor Van Boom and his organic chemistry laboratory 1 1
DNA synthesis and immobilization of nucleotides on cellulose 12
Second fellowship year: continuing enzyme substrate collaboration with Campagnari 13
First publications on small DNA molecules and synthesis of phosphates 13
Synthesis and coupling of seven or eight nucleotides 14
Van Boom s reputation in oligonucleotide synthesis 14
Crea s appointment as associate professor in 1976 14
Limited opportunities for young biochemists in Italy 14
Excitement of exploring uncharted science in Leiden 15
Introduction to High Performance Liquid Chromatographer 15
Friendship with Van Boom 1 5
Social, cultural, and intellectual context in Leiden 15
City of Hope Medical Center, Duarte, California, 1 977-1 978 16
Professor Rosch, Herbert Heyneker, and the connection with City of Hope 16
Keiichi Itakura s letter to Van Boom offering postdoc positions in his lab 17
Van Boom and Robert Swanson visit Itakura at City of Hope 1 7
Crea decides on a postdoctoral fellowship at City of Hope 17
Crea arrives in Los Angeles, May 1, 1977: first impressions 17
Arrival at City of Hope 1 9
First meeting with Keiichi Itakura 19
The Itakura laboratory, layout and personnel 19
Relationship with, funding from Genentech 20
Somatostatin 20
Project using recombinant DNA 20
Chemical synthesis of somatostatin gene 20
Re-synthesis of defective DNA fragments 20
High Performance Liquid Chromatographer for oligonucleotide purification 20
Itakura s administrative duties 21
Crea s responsibilities and contributions 21
Phosphodiester and phosphotri ester methods of oligonucleotide synthesis 2 1
Solving problem of somatostatin expression; Arthur Riggs s fusion protein approach 22
First production of a mammalian protein in bacteria 23
Wylie Vale s contribution of sheep somatostatin sequence 24
Tadaaki Hirose and contributions 24
Somatostatin project to establish Genentech vision and City of Hope partnership 25
Success brings international attention 25
Press conference, celebrating with Bob Swanson 25
Human insulin 25
Planning research on human insulin gene synthesis 25
Using dimer and trimer blocks for efficient construction of gene 26
Crea develops fast purification method 26
Adam Kraszewski joins group as postdoc and Crea s roommate 27
Dismissing health concerns in a scientific race for human insulin 27
Re-making a defective DNA fragment 27
Crea and Kraszewski paid by Genentech 28
Joining the A- and B-chains of insulin 28
Mini C-chain as backup experiment; first experiment in protein engineering 28
Crea s confidence that foreign genes will express protein in bacteria 29
Insulin gene designed for compatibility with bacterial genetic preference 29
Expression and purification of A- and B-chains 29
Riggs s lab assembles and characterizes human insulin chains 29
Scientific exchange/socialization with Riggs and Itakura labs 30
Boyer group s decision to use lac promotor and beta-gal gene in plasmid vector 30
Caltech contract and Genentech shares 3 1
Richard Scheller s attempt to synthesize double-stranded oligonucleotide 3 1
Scheller attempts to provide DNA for crystallography studies 3 1
Scheller s Genentech shares make him a millionaire at IPO 3 1
Crea s naivete re share value; Tom Perkins s advice 3 1
Corporate culture and controversy 32
Academics leaving for industry positions 32
Comparing academic and Genentech cultures 32
Genentech scientists drive biotech technology 32
Recombinant DNA controversy 33
Tom Perkins as Genentech board member, advisor, personality 33
First meeting with Shirlee Fox 34
Arrival at Genentech, fall 1978 35
Robert Swanson s offer letter 35
Swanson offers Crea a room in his apartment 35
Designing Genentech s laboratories 35
Setting up and staffing DNA synthesis laboratory 36
Bovine and human growth hormone 36
Synthetic DNA from City of Hope 35
Replacement of human codons with codons recognized by E. coli 36
Oligonucleotides made at City of Hope 36
More on insulin 37
Purification of chains 37
Making an insulin molecule identical to the human 37
Tricking the bacteria 38
Determining E. coli s codon preference 38
Eli Lilly 39
Drawbacks of bovine insulin 39
Demonstrating production of recombinant human insulin 39
Demonstrating production of protein-based drugs 40
Management 40
Pitching drug candidates to pharamceutical companies 40
Swanson accused of keeping employees in the dark 41
Board of directors 41
Lubrizol and Alfa Laval become members 41
Reasons for lack of a scientific board 41
Power in the scientific team 41
Crea s desire for scientific autonomy; Swanson s desire for recognized scientific experts 42
Crea s relationship with Swanson 43
Positives and negatives of hiring process 43
Insulin press conference 44
Technology s relevance to pharmaceutical industry and health care 44
Conference format and atmosphere 45
Expression and DNA synthesis papers on insulin 45
Submission and author order 46
Boyer s distancing from Genentech science 47
Criticism of Boyer s hybrid role in academia and business 47
High quality of Genentech science and publications 48
Riggs-Itakura patent 48
Conception and execution of research 49
City of Hope files for patent, rather than UCSF or Genentech 49
Genentech receives exclusive license rights 49
Intellectual property 50
Importance in biotechnology 50
Chakrabarty Supreme Court decision 51
Genentech projects ca. 1978 52
DNA synthesis laboratory 52
Relationship with City of Hope 52
Competition with outside labs 53
Human growth hormone 53
Peter Seeburg as collaborator 53
Contribution of City of Hope group 53
cDNA approach 53
Composite synthetic and natural gene 54
Increasing expression yields 54
Early scientific culture 54
Crea s solid-base synthesis 55
Genentech s goal to beat competition 55
Genentech s advantage in skills and tools 55
Cetus and Biogen as competitors 55
Monitoring literature and scientific meetings 57
Crucial information on interferon 57
Recruitment of scientists 5 8
Building Genentech s scientific reputation 58
Publication policy 58
Legal review for patentability 59
Insuring quality publications 59
Peer review 59
Financing 60
Private capital 60
Lilly contract 60
Venture capital vs. corporate funding 60
Pressure on scientists 60
Director of research on executive board 6 1
Extending/validating commercial application of genetic technologies 6 1
Bovine and human growth hormone as commercial products 62
Genentech positioned as future pharmaceutical company 63
Insulin provokes discussion of manufacturing issues 63
Noel Stebbing hired to introduce cell biology 63
Communication problems as Genentech grew 64
Crea s isolation from downstream development 64
More time on administration 64
Decline in inter-group communication 64
Gene machines and DNA synthesizers 64
Crea s interests shift from DNA synthesis to uses of DNA in molecular biology 65
Gene synthesis, cloning, and other applications in Crea s lab 65
Tensions with molecular biology division 65
Crea thinks of founding a company 66
Scientific directors 66
Initial Public Offering 66
Shares recognized as valuable asset 66
Genentech plays to investors 66
Remembering Wall Street opening 67
Monetary value becomes important 67
Newspaper headlines 67
Science as usual 68
Increased publicity, financial analysis 68
Thymosin project 69
Ron Wetzel s protein chemistry group 69
Use of computer modeling of proteins 70
Correlation of protein structure and function 70
Crea s research interests extend beyond DNA synthesis service function 70
Interest in gene and protein analogs 70
New ability to modify protein structure through gene synthesis 71
Early protein engineering at Genentech 7 1
More on thymosin, a curtailed project because of insufficient biological knowledge 71
Noel Stebbing and biology at Genentech 75
Giuseppe Miozzari as science representative to board of dirctors 76
Professor George Whitesides as consultant 76
Proinsulin project 76
Eli Lilly 77
Corporate focus shifts from cloning to protein synthesis to clinical development 78
Interferons 79
Kari Cantell s leucocyte sources 79
Race to identify genes 80
Genentech obtains fibroblast ammo acid sequence and secures the gene 80
Genentech s unique technological position 8 1
Partnership with Hoffmann-La Roche on leukocyte interferon 8 1
Importance of Genentech s dimer and trimer library 8 1
Confronting the redundancy of the genetic code 81
Discovering multiple interferon species 82
Amgen s consensus interferon 83
rDNA at Genentech not mere tool for protein synthesis but rather a tool for discovery 84
Crea s decision to leave Genentech 84
Crea limited to chemistry rather than discovery 84
Growing company size and administrative duties 85
Announcing decision to Swanson 85
Creative BioMolecules, Inc. 86
Lack of collaboration with Genentech 86
Developing intellectual property 87
Crea s contributions 87
TAPE GUIDE 89
APPENDDt 91
Curriculum Vitae 93
Bibliography 96
City of Hope Appointment Letter, May 16, 1977 100
Genentech Appointment Letter, February 10, 1978 101
Letter from Crea to J. Van Boom, May 4, 1978 102
Genentech Performance Review, November 26, 1980 103
Letter from Bob Swanson announcing Crea s departure from Genentech, October 9, 1981 105
Letter from Tom Kiley announcing first Genentech patent, January 15, 1982 106
INDEX 107
BIOTECHNOLOGY SERIES HISTORY-Sally Smith Hughes, Ph.D.
Genesis of the Program in the History of the Biological Sciences and Biotechnology
In 1996 The Bancroft Library launched the Program in the History of the Biological Sciences and
Biotechnology. The Bancroft has strong holdings in the history of the physical sciences-the papers of
E.O. Lawrence, Luis Alvarez, Edwin McMillan, and other campus figures in physics and chemistry, as
well as a number of related oral histories. Yet, although the university is located next to the greatest
concentration of biotechnology companies in the world, Bancroft had no coordinated program to
document the industry or its origins in academic biology.
When Charles Faulhaber arrived in 1995 as Bancroft s director, he agreed on the need to
establish a Bancroft program to capture and preserve the collective memory and papers of university and
corporate scientists and the pioneers who created the biotechnology industry. Documenting and
preserving the history of a science and industry which influences virtually every field of the life sciences
and generates constant public interest and controversy is vital for a proper understanding of science and
business in the late twentieth and early twenty-first centuries.
The Bancroft Library is the ideal location to carry out this historical endeavor. It offers the
combination of experienced oral history and archival personnel and technical resources to execute a
coordinated oral history and archival program. It has an established oral history series in the biological
sciences, an archival division called the History of Science and Technology Program, and the expertise to
develop comprehensive records management plans to safeguard the archives of individuals and
businesses making significant contributions to molecular biology and biotechnology. It also has
longstanding cooperative arrangements with UC San Francisco and Stanford University, the other
research universities in the San Francisco Bay Area.
In April 1996, Daniel E. Koshland, Jr. provided seed money for a center at The Bancroft Library
for historical research on the biological sciences and biotechnology. And then, in early 2001, the
Program in the History of the Biological Sciences and Biotechnology was given great impetus by
Genentech s major pledge to support documentation of the biotechnology industry.
Thanks to these generous gifts, the Bancroft has been building an integrated collection of
research materialsoral history transcripts, personal papers, and archival collectionsrelated to the
history of the biological sciences and biotechnology in university and industry settings. A board
composed of distinguished figures in academia and industry advises on the direction of the oral history
and archival components. The Program s initial concentration is on the San Francisco Bay Area and
northern California. But its ultimate aim is to document the growth of molecular biology as an
independent field of the life sciences, and the subsequent revolution which established biotechnology as
a key contribution of American science and industry.
Oral History Process
The oral history methodology used in this program is that of the Regional Oral History Office,
founded in 1954 and producer of over 2,000 oral histories. The method consists of research in primary
and secondary sources; systematic recorded interviews; transcription, light editing by the interviewer,
and review and approval by the interviewee; library deposition of bound volumes of transcripts with table
of contents, introduction, interview history, and index; cataloging in UC Berkeley and national online
library networks; and publicity through ROHO news releases and announcements in scientific, medical,
and historical journals and newsletters and via the ROHO and UCSF Library Web pages.
11
Oral history as a historical technique has been faulted for its reliance on the vagaries of memory,
its distance from the events discussed, and its subjectivity. All three criticisms are valid; hence the
necessity for using oral history documents in conjunction with other sources in order to reach a
reasonable historical interpretation. 1 Yet these acknowledged weaknesses of oral history, particularly its
subjectivity, are also its strength. Often individual perspectives provide information unobtainable
through more traditional sources. Oral history in skillful hands provides the context in which events
occur-the social, political, economic, and institutional forces which shape the course of events. It also
places a personal face on history which not only enlivens past events but also helps to explain how
individuals affect historical developments.
Emerging Themes
Although the oral history program is still in its initial phase, several themes are emerging. One is
"technology transfer," the complicated process by which scientific discovery moves from the university
laboratory to industry where it contributes to the manufacture of commercial products. The oral histories
show that this trajectory is seldom a linear process, but rather is influenced by institutional and personal
relationships, financial and political climate, and so on.
Another theme is the importance of personality in the conduct of science and business. These
oral histories testify to the fact that who you are, what you have and have not achieved, whom you know,
and how you relate have repercussions for the success or failure of an enterprise, whether scientific or
commercial. Oral history is probably better than any other methodology for documenting these personal
dimensions of history. Its vivid descriptions of personalities and events not only make history vital and
engaging, but also contribute to an understanding of why circumstances occurred in the manner they did.
Molecular biology and biotechnology are fields with high scientific and commercial stakes. As
one might expect, the oral histories reveal the complex interweaving of scientific, business, social, and
personal factors shaping these fields. The expectation is that the oral histories will serve as fertile ground
for research by present and future scholars interested in any number of different aspects of this rich and
fascinating history.
Location of the Oral Histories
Copies of the oral histories are available at the Bancroft, UCSF, and UCLA libraries. They also
may be purchased at cost through the Regional Oral History Office. Some of the oral histories, with
more to come, are available on The Bancroft Library s History of the Biological Sciences and
Biotechnology Website: http://bancroft.berkeley.edu/Biotech/.
Sally Smith Hughes, Ph.D.
Historian of Science
Regional Oral History Office
The Bancroft Library
University of California, Berkeley
October 2002
1 The three criticisms leveled at oral history also apply in many cases to other types of documentary
sources.
Ill
January 2004
ORAL HISTORIES ON BIOTECHNOLOGY
Program in the History of the Biological Sciences and Biotechnology
Regional Oral History Office, The Bancroft Library
University of California, Berkeley
Paul Berg, Ph.D., A Stanford Professor s Career in Biochemistry, Science Politics, and the Biotechnology
Industry, 2000
Mary Betlach, Ph.D., Early Cloning and Recombinant DNA Technology at Herbert W. Bayer s UCSF
Laboratory, 2002
Herbert W. Boyer, Ph.D., Recombinant DNA Science at UCSF and Its Commercialization at Genentech, 2001
Roberto Crea, DNA Chemistry at the Dawn of Commercial Biotechnology, 2004
David V. Goeddel, Ph.D., Scientist at Genentech, CEO at Tularik, 2003
Thomas J. Kiley, Genentech Legal Counsel and Vice President, 1976-1988, and Entrepreneur, 2002
Dennis G. Kleid, Ph.D., Scientist and Patent Agent at Genentech, 2002
Arthur Kornberg, M.D., Biochemistry at Stanford, Biotechnology at DNAX, 1998
Fred A. Middleton, First Chief Financial Officer at Genentech, 1978-1984, 2002
Thomas J. Perkins, Kleiner Perkins, Venture Capital, and the Chairmanship of Genentech, 1976-1995, 2002
G. Kirk Raab, CEO at Genentech, 1990-1995, 2003
Regional Characteristics of Biotechnology in the United States: Perspectives of Three Industry Insiders (Hugh
D Andrade, David Holveck, and Edward Penhoet), 2001
Niels Reimers, Stanford s Office of Technology Licensing and the Cohen/Boyer Cloning Patents, 1998
William J. Rutter, Ph.D., The Department of Biochemistry and the Molecular Approach to Biomedicine at the
University of California, San Francisco, volume I, 1998
Richard Scheller, Ph.D., Conducting Research in Academia, Directing Research at Genentech, 2002
Robert A. Swanson, Co-founder, CEO, and Chairman of Genentech, 1976-1996, 2001
Daniel G. Yansura, Senior Scientist at Genentech, 2002
iv
Oral histories in process:
Moshe Alafi
Brook Byers
Ronald Cape
Stanley N.Cohen
Donald Glaser
Herbert Heyneker
Irving Johnson
Daniel E. Koshland, Jr.
Lawrence Lasky
Arthur Levinson
Diane Pennica
George Rathmann
Steven Rosenberg
William J. Rutter, volume JJ
Axel Ullrich
Mickey Urdea
Pablo Valenzuela
Keith R. Yamamoto
INTERVIEW HISTORY-Roberto Crea
DNA synthesis capability are the three words which tersely explain Crea s trajectory from the
University of Leiden to southern California and then on to Genentech in 1978. He was among the
first scientists hired by Genentech as it opened its unprepossessing facility in South San Francisco.
But Crea s connections with Genentech antedated his arrival by more than a year. He honed his
expertise in the chemical synthesis of DNA at the City of Hope Medical Center, outside Los
Angeles, in the laboratory of Keiichi Itakura, one of the few experts in this then arcane field. He
became a member of the Genentech-supported UCSF-City of Hope team bent on demonstrating
that bacteria could be engineered to produce proteins from non-indigenous sources. In 1977 the
collaborators announced that they had induced bacteria to express the mammalian protein
somatostatin. It was a spectacular proof-of-principle experiment that indicated the commercial
potential of the new genetic technologies of recombinant DNA and DNA synthesis. From there
the team went on to achieve a similar feat in the production of human insulin.
Crea tells in this oral history of his contribution to these early successes, the background and
response to the somatostatin, insulin, and growth hormone work, his formation of a DNA synthesis
group at Genentech, and considerably more. What Crea makes abundantly clear is the advantage
that DNA synthesis capacity gave to Genentech at a time when no other company had the
technology. He also suggests the gung-ho, highly competitive, youth culture of Genentech. The
attitude to just about everything was, as Crea puts it: "Let s go for the Big Enchilada." But all was
not sweetness and light. In 1981, wishing to stretch his own wings, Crea left Genentech and went
on to found the first of several companies. He is today the founder and chairman of a company
producing antioxidants from olive oil.
Oral History Process
Five interviews were conducted in Dr. Crea s office in Hayward, California, adjoining the plant
which produces olive oil from which several products are derived. The company is one of three
with which Crea is currently associated as founder. He spoke in fluent English stamped with the
accent of southern Italy, land of his origins. He carefully reviewed the interview transcripts, at first
making numerous changes which after the first chapter dropped to a minimum. By agreement with
Genentech regarding the oral histories it supports, its legal department received transcripts of all
interviews to review solely for current legal issues. As in all other instances to date, no changes
were requested.
The Regional Oral History Office was established in 1954 to augment through tape-recorded
memoirs the Library s materials on the history of California and the West. Copies of all the
interviews are available for research use in The Bancroft Library and in the UCLA Department of
Special collections. The office is under the direction of Richard Candida Smith, Director, and the
administrative direction of Charles B. Faulhaber, James D. Hart Director of The Bancroft Library,
University of California, Berkeley. The catalogue of th Regional Oral History Office and many
online oral histories can be accessed at http://library.berkeley.edu/BANC/ROHO. Online
VI
information about the Program in the History of the Biological Sciences and Biotechnology can be
accessed at http://library.berkeley.edu/BANC/Biotech/.
Sally Smith Hughes, Ph.D.
Historian of Science
Regional Oral History Office
The Bancroft Library
University of California, Berkeley
January 2004
vii
Regional Oral History Office
Room 486 The Bancroft Library
University of California
Berkeley, California 94720
BIOGRAPHICAL INFORM iTION
(Please write clearly. Use bit ;:k ink.)
Your full name
Date of birth 7UlV I
Father s full name
Occupation
Birthplace
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Birthplace fi ix=Cg L-JV
Mother s full name
Occupation
Your spouse/partner
Occupation
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Birthplace^. CATAlfJA .^S
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Birthplace _ ^
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Your children
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Where did you grow up
Present community S.
Education
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Occupation(s)
Areas of expertise ])^ fr _ M<?leC,
Other interests or activities
Organizations in which yo re active
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SIGNATURE
DATE MP- (S. leo 3
INTERVIEW WITH ROBERTO CREA
[Interview 1: June 27, 2002] ##
Hughes: Dr. Crea, would you tell me a little about your family background, beginning with your
grandparents on both sides?
Crea: I didn t have the fortune to meet my grandparents. When I was bom, my grandparents,
from my mother s side as well as my father s side, were dead. My grandparents from my
mother s side both died by diabetes, a distance of one year. My grandfather, Bruno Milea,
died first, and then exactly one year later, my grandmother, Caterina, died. I imagine that
at that time diabetes was a disease which wasn t easily treated. I know a little bit of my
grandfather from my mother s side, from what my mother told me and from my relatives.
My grandfather was a businessman in Calabria, southern Italy. He was a very intelligent
entrepreneurial person who had built a very strong position in the field of essential oils
extraction (extraction of essential oils).
Calabria and many other regions of southern Italy are famous for their warm climate,
almost like California. So, there are a lot of flowers and citruses. A hundred years ago
there was a group of entrepreneurs who had started extracting the essential oil from the
flowers of orange trees and lemon trees and other flowers like jasmine. They were selling
the oil to cosmetic companies all over the world, including the United States. For
instance, I learned that my grandfather came to the United States when my mother was
still a young girl, for business reasons, which was very unusual because travel was so
difficult. He had to travel by carriage from southern Italy to Rome, most likely by train
from Rome to other European countries, and I m sure that he traveled by cruise ship to
the United States. I think some of my entrepreneurial skills come from that side of the
family.
My mother, Giuseppina Milea, was the youngest of five kids two boys and three girls.
Her family, as I said, were fairly rich for people at that time. They had a lot of houses and
land. Unfortunately, that didn t help her, because after the death of her parents, my
grandparents, she was the last of five kids who were quite young and inexperienced in
taking over a situation which hadn t been planned. As a matter of fact, the business side,
the company and most of the real estate assets, went to the two brothers. At that time the
law in Italy was such that in case of death of the head of the family, the assets would go to
the boys. So my mother ended up with nothing. On top of that, she got married very
young. My father, Francesco Crea, wasn t coming from a similarly rich family, so the two
brothers didn t look at the marriage in a positive way. So my parents had to struggle to
raise a family.
My mother passed away this past April, at eighty-six years old. My father is still alive,
eighty-seven years old, and he has worked for his entire life in the railway business, as an
employee of the state, Italian Railway. In retrospect, I understand that it wasn t easy for
them to raise four kids and provide for all the necessary support for kids to go to school,
which we all did. We went to elementary school, which at the time in Italy was five years.
After, there were three years of intermediate school, and then there was high school for
five additional years. All the kids in my family had the chance to attend schools.
I started school, as many other kids in the South, in a small village in Calabria where my
father was working in a central electrical power station, providing the technical support
for the trains to move around. That was his expertise. Then after the elementary school, as
I started the intermediate school, my family moved from this small village in Calabria,
called Scalea. They moved back to Reggio Calabria. We ended up living in a small
village in the periphery of Reggio Calabria, which at that time was the capital of the
Calabria region. We lived in the Gallico Marina, which was about five miles away from
the city s downtown. I attended the intermediate school and high school in Reggio
Calabria.
I finished my high school in 1968. 1 took the scientific direction. I attended a scientific
lyceum rather than the classics lyceum. The classics lyceum is a high school where you
study more of the classics field, like Latin, Greek. The scientific lyceum provides more of
the scientific disciplines, like mathematics, physics, some focus on elemental biology.
Hughes: Why did you go in the scientific direction?
Crea: I felt that I was more inclined to science than classic studies. I particularly enjoyed
mathematics and the logics behind the scientific disciplines. My sister chose the classics.
She then became a teacher of Latin and Greek languages in high school. I didn t want to
do that. I was the last of four kids two brothers and one sister, then me. I was the
youngest of the family and as such I enjoyed more freedom than the rest of my siblings.
My early interest was for mechanical engineering, and I never thought that I would
become a chemist. I always wanted as a child to build boats and ships. My ideal of a
career was to become an engineer for building big boats.
Hughes: What were your parents saying about these ambitions?
Crea: Well, they were obviously listening to me, although they were more preoccupied to see
me doing well in early school, which I was doing.
Hughes: Were you the student of the family?
Crea: My sister and I were essentially the most brilliant of the family. My first brother never
really managed to accomplish a brilliant academic career. My second brother stopped
going to school after getting a diploma as a technical engineer. It s a low degree, but it
allows people to start working in some sort of trade.
Hughes: Would that be the counterpart of a vocational high school degree?
Crea: Yes. So, my sister and I were the only two kids to pursue university studies. My sister got
a doctoral degree in human sciences, and I ended up studying chemistry. That came later.
My dream was to finish high school in Calabria and then to move to northern Italy, in
Piedmonte, in Turin, where there is one of the best engineering schools. The reason I was
hoping to get to Turin was that I had an uncle who moved with his family to Turin many
years earlier, so I had a place to go. Obviously, I was hoping to minimize the cost of
moving from my family to go study in a different place.
Hughes: So there wasn t a lot of money for your education?
Crea: Well, for the education up to high school I attended public schools. We were paying
tuition every year. But in Italy, it s fairly accessible to everybody, so it wasn t until I
started the university that the financial issue started becoming important. In a way, I
managed to minimize the financial burden for my parents by getting the high school
degree with a high score. That allowed me to apply for a grant in a university, which I
obtained early on, so I was essentially supporting myself from day one. That grant would
allow me to stay in the city where I was attending university, which was a city in Sicily
just across the Strait of Messina. I was commuting every day, waking up early in the
morning, catching a train to the place where the ferries would commute back and forth,
go to the university to attend lessons, and in the late afternoon, catch a ferry and go back
home. It was very tiring because I would get up early, like six o clock, and come back
eight o clock in the evening, exhausted, and the day after I would do the same.
So, after a year or so of commuting, I found a boarding room in Sicily, near the
University of Messina, and I was staying there five days a week. Then, Friday afternoon I
would come back to my parents house near Reggio Calabria and then start again the
following Monday.
Hughes: Were you making friends?
Crea: Yes, a lot of friends. In Italy, especially in southern Italy, there s plenty of opportunity to
socialize. We were finding ourselves together on the train, on a ferry, in the cafeteria of
the university so a lot of friends. Also, I was part of the Youth Catholic movement.
Actually, since I was a kid I was educated Catholic, so I attended church. That has had an
effect on me. I was also serving Mass when I was a kid, and I was part of the Catholic
movement.
Hughes: What do you mean by "Catholic movement"?
Crea: Well, there is a church organization in Italy which favors the young groups who are
interested in church affairs. It s called Azione Cattolica. It s like the Boy Scouts
association, but less formal. We didn t have uniforms, but we belonged to an organized
group of young Catholics. It was, among other things, an experience to meet friends, meet
girls, play games. I became more involved as I grew up, because I started to attend
national events. I became an educator of young kids. Educator means somebody like a
mentor, somebody who can teach the Catechism, somebody who deals with young
people s problems, coaches them in sports and in life, as well. So, I was very motivated at
that time to learn more about the Catholic Church and the religion as well.
Hughes: Was your family religious?
Crea: Yes. Well, most Italian families are Catholics, although my father never professed
himself as Catholic. The rest of the family pretty much followed a routine in Italy, where
you go to church, you learn that you are bom Catholic. If you find the right motivation,
you start associating with other groups of people to learn more about the religion as well
as create a style of life. It s a way of life, not different from other people s, but in the
context of a Catholic association, you do certain things. You are supposed to go to Mass,
you learn about the novelties in the doctrine, you dig into the religion and try to be a good
Catholic.
Hughes: Do you consider yourself today to be a good Catholic?
Crea: No, I lost that drive long ago. In part it is because most of it was dictated by the social
context. You feel part of a community. Once you leave your community, you end up
living in a new environment where you don t know many people; you don t have friends
of many years. You get busy doing other things. In my case, that strong interest which I
had for religion transformed soon into a strong interest for science. Not that the two
things cannot live together, but time was very limited, especially when I had to work hard
in order to finish my degree.
Hughes: Did that transformation begin to happen when you were in university?
Crea: Yes, correct. It started as a gradual moving away from religion when I moved from
University of Messina. It was 1970, so I was twenty-two years old. I moved to northern
Italy to start my final university studies. That decision was mainly dictated by the desire
to leam more about biochemistry and later on molecular biology. So, it was very much
related to the studies I was attending. But in reality it put me in a situation where I lost
most of the contacts with my community and friends. Then I had to struggle to survive on
my own in a new environment.
To the extent that I was going back to Reggio and my family, I was always part of that
community. Recently I went back to Calabria after many years for the funeral of my
mother, and I saw very old friends. It wasn t much changed. It was the same spirit. I had
dinner with my friend priests. As I said, I was very much involved in the Catholic
movement. When I was young, I had the chance to meet a lot of priests and travel with
them in Italy. At dinner, we remembered the good old times when we were going to
summer camps and educating kids. I felt I had lost in all these past years the opportunity
to be an active Catholic. But the spirit of friendship and respect and love for one another
has not changed, and that is part of the way you grow up and the way you get educated.
Hughes: Before we leave your first family, tell me a little about the quality of family life. Did you
spend a lot of time together?
Crea: Well, as I said, my family was a modest family in that we were all depending on my
father s salary as a railway worker. But it was a family that grew up with a lot of dignity.
We were what you would call middle class. We used to live in one apartment, which was
provided by the state railway company. There were sixteen apartments in two buildings,
so there were lots of opportunities to familiarize with other kids from a similar family
situation. I never felt any discrimination based on my family. On the contrary, I spent
most of my early youth in a serene environment in a village where the economy was
pretty much linked to jobs belonging to a state railway.
So, my early years were spent in a family which in part was struggling financially; we
were living in the postwar years. It wasn t until the sixties that families of the middle
class in Italy started getting more of a financial benefit. But until then, we were
struggling. My mother was trying to dress us well, feed us well, but never in excess of
course. We were sharing. We were aware of the financial situation of the family, but we
were still finding plenty of times to be happy with other kids, playing with our co-eds
downstairs in the front yard of the building, playing soccer, or running in the wild in the
little hills surrounding the building. There was plenty of opportunity for very happy years
with no conflicts of any sort, other than the feelings of an overall modest financial
situation.
Hughes: Were you close to your brothers and sisters?
Crea: I was closer to my sister, Palma. She was the third. The difference between myself and
my sister is only three years, while my two brothers are kind of different generation. They
were living growing pains much earlier than I was, in terms of meeting girls and hanging
out with the co-eds. So, for me, being the youngest in the family, it was more enjoying the
freedom, because I had fewer responsibilities than the other brothers. But sometimes I
was always getting the short end of the stick in terms of allowances, for instance. I was
getting enough to go to the movie on Saturday and that was it. I had a little money to buy
myself ice cream when I was going to school, but the rest was up to my mother to manage
the financial situation. I never complained.
Perhaps I learned early on that the lack of financial means in the family can create
conflicts, and there were conflicts between my older brother and my father. Very often I
would witness quarreling back and forth about how we were spending money and the
need of saving. For the young of us, it was normal; we didn t have any other yardstick,
any other comparison, so we did the best we could. I didn t particularly enjoy being
mistreated by my older brother, sometimes being told to do the dirty jobs, having to obey
and shut up just because I was the little one. Other than that, I spent a lot of my free time
outside the family. Not that we were not close to each other, but each one was too busy
going to school during the day. When we came back from school, everybody was going
in his or her direction. I was going to see my friends and playing with them.
n
Crea: Sometimes my parents couldn t afford to buy new shoes. Sometimes you had to wear
your older brother s clothes. Things like that, but other than that we were living well in
that small village in southern Italy. Watching television for us was magic, maybe not in
my house, because we couldn t afford it until I was adolescent. But to go next door to
another family with a television and watch the early programs, sometimes things that
were coming from the United States like Rin Tin Tin in black and white, was fascinating.
Hughes: Well, once you got to Messina, you started a course in chemistry. Why chemistry?
Crea: I was ready to move from Reggio Calabria to Turin when I finished my high school. But
in the summer following my graduation, my uncle died by a freak accident. He was in the
police, and somehow he got killed by gunshot. We never knew whether it was an accident
or more than that. It was a trauma for everybody to lose my uncle. For me, it was out of
the question to move away from the family under those circumstances. So, I was kind of
disoriented. My father, as often, came up with a beautiful suggestion, which I accepted
because I didn t have any real alternative. My father suggested that I start chemistry at the
University of Messina because chemists were in high demand by the industry at that time,
and I could most likely get a job at the end of the university.
Hughes: Chemistry, as opposed to engineering?
Crea: As opposed to engineering. There was no good engineering school in Messina. Chemistry
was a very good faculty. To be honest with you, I didn t know what chemistry was all
about when I started, but I accepted it as kind of "This is my destiny. Now let s start." I
don t want to lose any time. So, I went to Messina and enrolled myself and started
chemistry the following fall. That was really a big trauma for me, not only because I had
to commute it wasn t easy to commute but also I didn t quite understand anything
about chemical reactions. It was a completely brand-new world. I had never done
anything at high school to be prepared for the lessons and the learning that I was going
through, so it was really very hard. As a result, the first two tests that I took were
mediocre. The first score was twenty-one out of thirty, and the second one was eighteen
out of thirty, which was the bare minimum. Of course, I thought that the professor had
been unfair, because I had worked very hard to learn as much as I could.
In general, I can say that the first three years of the university weren t happy ones, besides
being away from my friends, my family, my first girlfriend, as well. I had a lot of troubles
seeing myself in the laboratory, concocting reactions with bad smell and long hours,
things that didn t mean that much to me. So it was like, okay, if I had to do this, let s do it.
I ll try to do my best. But there was no passion to what I was doing.
Hughes: What about the chemistry faculty?
Crea: The faculty was a good one. There were some good professors and some bad professors.
Probably the first year in chemistry, there were about one hundred students attending
lessons. It was clear the second year and the third year, the number had to be dropped
dramatically. It was a tough faculty. The degree in chemistry was considered to be one of
the most difficult ones. There were thirty different exams in order to go through. In Italy,
as you know, the university is different from here in that it is a mix between Ph.D. and
master degrees. You do almost a Ph.D., because at the end of the studies you write a
thesis and do experimental work. So, it was like a grim perspective, and that grim
perspective was in part compensated by the fact that I met new friends in Messina. It was
a new world, more independence. It was part of the growing-up process. It was a heart-
shaking experience in that I was very insecure, vulnerable. Financially I wasn t well
taken care of. I had this responsibility to do well, because I couldn t fail and create an
additional burden to my family. I wanted to do well, because my idea was, well, if
chemistry was all there is, I might as well finish as fast as I can and move on.
And then something suddenly happened in the third year of university: I enjoyed very
much attending biochemistry. Biochemistry was for me almost a miracle. It was not only
because finally I was learning something interesting about living organisms, but also a
great professor was teaching biochemistry. That professor, Mr. Giovanni Cuzzocrea, was
a fantastic teacher, a gentleman, and a visionary. So, I fell in love with biochemistry.
Finally there was something that I really could develop a passion for.
Unfortunately, that faculty had only one or two courses related to biochemistry, so it was
clear early on that I had to look somewhere else, other than Messina, to continue learning
and building my knowledge in biochemistry. So, what I did after I passed the test, of
course, with maximum scores thirty plus laude, thirty is the maximum score, plus the
laude which is an extra reward, I asked my professor to drive me in this decision-making
process to continue my career in biochemistry. Professor Giovanni Cuzzocrea told me
that I had to leave Messina if I really wanted to do more. That wasn t surprising to me; I
had already made that decision myself. I remember he gave me three letters. He said,
"During the summer break, why don t you take a week or two and go visit these three
friends of mine who are heads of laboratories in northern Italy and talk with them. They
might decide to accept you in their laboratory, in which case you will continue in
biochemistry and maybe you can also write a thesis in biochemistry."
That is exactly what occurred. In 1970, 1 visited two of the three and the second one,
Prof. Alessandro Castellani, was in Pavia. He was so interested in my desire to do more in
biochemistry that he offered me an internship in his laboratory. So, I finished the
remaining exams in Messina very quickly because I wanted to finish all the third year
tests and then go to Pavia.
I moved to Pavia in the fall of 1970, and I start attending the laboratory of Professor
Castellani. He was the head of the biological chemistry department in the University of
Pavia, which is a prestigious university in Italy. It s located near Milan and is one of the
oldest medical schools and universities. It was formed by Cardinal Borromeo and the
church in the late eighteenth century. So it had a great tradition. I realized when I went to
Pavia that it was almost like being in Cambridge, England. It was a lot of bright people,
living in colleges, like in Oxford. It was really an intellectual elite as compared to
southern Italy.
Hughes: Had you passed entrance exams? How had you gotten in there?
Crea: Well, no. There was a lucky circumstance. The year I decide to move was also the year
where the Ministry of Scientific Affairs of Italy had introduced a new law which in
essence allowed students to move freely from one university to another.
Hughes: Do you know the circumstances for that law?
Crea: Well, they wanted to make it easier for students to leam from different universities. They
introduced the concept of "Piano di studio," a plan for your academic career. If your plan
was acceptable to another university, in theory, you could move and start studying there.
Again, let s not forget that universities in Italy still are state institutions. They are not
private institutions, so it was easier to move from one university to another. So, I had my
piano di studio and I presented it to Professor Castellani and the faculty. I have been very
grateful to Professor Castellani for accommodating my aspirations by letting me work in
his laboratory. I finished the course in chemistry in Pavia by taking the exams of the
fourth and fifth year without a glitch. I also worked on my experimental thesis, and I
graduated with a doctoral degree in chemistry in 1972.
I did very well in Pavia. It was strange for me. It was my first experience in the
laboratory, but I did very well because I had a very intelligent teacher, a supervisor, who
ultimately ended up taking over Professor Castellani s position. His name is Cesare
Balduini. Professor Balduini directed me toward very interesting research. I was working
on cartilage metabolism and cartilage diseases. Early on, I was cracking eggs with
newborn chicks, and in a very tedious fashion I would pull out one by one the tibias,
which is the leg s long bone, out of these little creatures and put them in ice. When I had
collected enough, maybe a couple of grams, I would homogenize these little bones. I
would crush them in a blender to create a homogeneous collagen suspension, and that
was my starting material.
As we got more sophisticated, instead of going in the morning to fetch fertilized eggs, I
would go for newborn pigs, which was a little more gruesome. I would go to the farm
and get two or three newborn piglets, bring them back to the laboratory. The poor
creatures would be anesthetized and killed. Then, I would remove some of the bones and
scratched the thin layer of cartilage between them. That was my starting material for the
experimental studies needed for my thesis. After a few weeks, I learnt how to cope with
this unpleasant situation. The research work was fairly interesting and successful
because as I studied the enzymatic components of the cartilage at an early stage, we
found some new enzymatic activities.
Hughes: That was unexpected?
Crea: Yes. I managed to develop a new method for the fractionation of the various intracellular
components of the cartilage. I was one of the few students in Italy capable of isolating
the rough reticulum from the smooth reticulum from the plasma membrane from cartilage
cells. So, we had really developed an interesting fractionation of the cartilage into
components, and we could study now the enzymatic activity associated with the different
membrane components. It was fascinating to me. I did write my doctoral thesis on this.
I also used the experimental data of my work to prepare my first oral presentation at my
first scientific symposium in Italy, which was kind of unique because I wasn t even
graduated when I spoke at the symposium. So, obviously I was talented enough for
Professors Castellani and Balduini to keep me involved with the laboratory, because there
was competition by more qualified students coming from Pavia s prestigious colleges.
That was the work I did for my thesis, which I presented the day of the graduation and
discussed it the way they do in other European universities and here in the U.S. for the
Ph.D. degree. I got a very high score. I graduated with one hundred and seven out of one
hundred and ten. I would have achieved the maximum if I didn t have the early bad
scores from Messina. So, I paid for that. But in the end not only I managed to graduate,
but also I managed to stay involved with the laboratory of Professor Castellani because
they appreciated my laboratory skills and my way of thinking creatively.
Hughes: Do you consider yourself to be good technically with your hands?
Crea: Yes, very good. Later on, a famous professor in Holland described me as the chemist
with golden hands, [laughs]. So, I think I m pretty good experimentally.
Hughes: Did you have any idea from any past experiences that you would be a good
experimentalist?
Crea: No. I had no idea that I was going be very comfortable with my hands. Also I found
myself intrigued in learning what other people were doing. Everything was some sort of
discovery. In high school and university you re used to studying books. You have to
memorize a lot of things and then you have to answer the questions when you take the
test. I remember one of the toughest exams was organic chemistry. We had to study
from five books, including the famous U.S. book, Boyd and Boyd, which was a thick
book, five inches of chemical reaction. You had to memorize everything because you
couldn t miss anything for your exam. Then, when you take the test and the professor
says, "Write the reaction between this chemical and whatever," you have to remember
that reaction. So, I was glad to move from memory to experiments in Pavia. I was happy
to set up experiments, and I was pretty good, I guess, designing the right experimental
condition to generate useful information.
Hughes: Who decided that cartilage would be your research topic?
Crea: It was Professor Castellani, who had trained in Chicago in early years. This laboratory in
the U.S. was focused on cartilage and disease of cartilage. It was very important field
because the University of Pavia has a very strong medical school and many collaborative
projects with hospitals. Some of my more senior colleagues in Pavia were working
together with M.D. s and clinicians at the hospitals to understand the pathology
underlying cartilage diseases. So there really was a medical component which made our
research more interesting and focused.
I was pretty happy in Pavia, although the weather was miserable. It is a city where you
have fog six months a year and humidity the remaining six, with a lot of mosquitoes in
the summer, [tape interruption]
Hughes: When did your interest in molecular biology emerge?
Crea: When I was still involved with the laboratory of Professor Castellani at the University of
Pavia, after graduation, I was interested in learning more about new areas of science. My
interests coincided with the fact that the science faculties, of which my biological
chemistry department was a part, decided to establish a three-year post-graduation
course, like a Ph.D., although there was no Ph.D. title per se. Part of this specialty three-
year course was the study of molecular biology.
I was extremely fortunate to meet a professor who was back from the United States, from
Cleveland. His name is Professor Francesco Campagnari. Professor Campagnari was a
really bright scientist, very passionate about research. He was one of the professors who
was going to teach the specialty course. I enrolled immediately and started attending
lectures held by Professor Campagnari, and next I found myself extremely interested in
the new concept of DNA, polymerase, gene replications. Campagnari had a background
in biochemistry, and he had several years of experience in Cleveland, at the Case Western
University, studying the replication of DNA. At that time that was the big novelty
coming from the United States, especially from Stanford and the work of Arthur
Komberg. It was really intriguing to learn the enzymatic mechanisms responsible for the
duplication of DNA, but also for the formation of messenger RNA. It was really exciting
to leam the most intimate cellular mechanisms. So, I jumped on this immediately.
Hughes: Was that your first exposure?
Crea: It was my first exposure to learning about the enzymes involved in DNA replication.
Hughes: How unique was that course?
Crea: It was very unique. It was the first in Italy. It was just the first year that they had started,
so I was there at the right time.
Hughes: That would have been 1973?
10
Crea: Correct. I really established a good relationship with Professor Campagnari, because I
was helping him produce transparencies, pictures out of books and other teaching
material. I was almost his right arm. He really appreciated my enthusiasm. Professor
Campagnari had his own laboratory in a little town called Ispra, near Varese, which was a
European laboratory. It was called Euratom.
m
Crea: While I was involved in the laboratory of Professor Castellani, I had managed to get a
grant from a prestigious organization, called the Academy of Linceii. It s an old Italian
scientific association. They were paying me about 1 .2 million liras a year, which was the
equivalent of about a few hundred dollars a month. With that salary I had to pay for the
apartment, transportation, and live on it. As a matter of fact, during the first years of
postgraduate work in Pavia, I was the only graduate waiter at a very popular dancing pub
just outside the city. I was trying to survive, believe me, and I didn t want to ask my
family for financial support.
I remember an episode which I never forgot: one day I parked my car in the wrong place,
and they gave me a ticket which was a third of my salary. In that case, I had to call my
family and say, "Help me, because this month, I m not going to make it." It was tough. I
was a young graduate student trying to fit into an academic system which was very
competitive with other graduate students, perhaps with more credentials than mine. So, I
was doing okay and never complained.
When I met Professor Campagnari, however, I talked to him about my precarious
situation with the University of Pavia I was an assistant professor, in effect. I asked him
if he had a job in his laboratory group in Ispra. Professor Campagnari really wanted to
give me a job in his lab, but he didn t have any opening. He suggested a couple of things,
which ultimately turned out to be crucial for my career. He suggested that as I was
waiting for a position in his group I should apply for a research grant with the European
Community and try to spend a couple of years in other European laboratories where I
could learn some techniques which eventually would be useful to his laboratory and his
research at Ispra. When I asked Professor Campagnari, if he could suggest such
laboratories in Europe, he said, "Let me tell you. There are two laboratories where I
would go if I were in your shoes. One is in Paris and the other is in Leiden, Holland. The
one in Paris, you leam more of the molecular biology techniques and the DNA
enzymology. In Holland, you learn more of the DNA chemistry." For me it was, "Well,
I don t have any way to decide. What would you suggest?"
He said, "The group in Holland is very innovative. They re doing something that is
extremely important and novel, because they are synthesizing DNA fragments, small
pieces of DNA, by chemical means. They are doing it under the leadership of this young
professor, Jacques Van Boom, who is a rising star in Europe. I would go there, because
you are a chemist and your background is in chemistry. If you leam how to synthesize
these molecules, then we have a better chance to learn how these enzymes work." It was
a perfect, logical, rational presentation!
So, I agreed with him. I said, "Maybe I ll go to Holland and leam DNA chemistry, and
we ll write together a scientific plan, so that I can produce some molecules that you can
use in your laboratory. When you are ready, I ll come back to work for you at Ispra."
11
We made the first request to one of the scientific agencies of the European Community,
called EMBO, the European Molecular Biology Organization, which is one of the major
European organizations that sponsor inter-country studies. So we made a request for me
to go to Leiden, and we got a quick rejection. It said, "Unfortunately, we don t have any
money available at the moment, so you have to wait." That was 1973. The second year, I
continued in Pavia, with the hope that I would get this grant. If I remember well, I finally
got a telegram from the European Community which was confirming my request had
been accepted and that I had to get ready to go on short notice. That was December,
1973.
I remember I got the good news while I was spending some time with my parents in
Calabria, because it was Christmas. When I got that telegram I was extremely excited.
My parents weren t so excited because I was going to Holland away from them. But,
once more, they were happy for me that I was moving ahead with my career. It was going
to be one year or maybe two years and then I would come back to Italy.
And that was the beginning of my career outside of Italy. The grant was from January 1,
1974 to the end of December, 1974. 1 remember Professor Campagnari said, "Well, one
thing I don t like in this" I said, "What, Professor?" "Well, you are going to make a lot
more money than you do right now, and I m afraid that you are going to get spoiled." The
European Commission has to pay good salaries in accordance to the European standard. I
said, "Well, that s a good problem to have, especially after two years of misery." So, I
loaded everything I had in one small car, a Citroen which they used to call "the Duck,"
which I had purchased in Pavia, and I took off for new frontiers.
Hughes: Had you been out of Italy?
Crea: Never. It was fascinating. I was driving, by myself, this overloaded car, over the Alps. I
was driving this poor ugly car, probably at forty-five miles an hour, with all those big
trucks behind me when I crossed Austria. It was beautiful in the late morning. Then I got
into Germany, which was a terrible experience. The freeways in Germany are crowded
with a lot of traffic. By then, I was in the first true adventure of my life. After twelve
hours of driving, I ended up stopping in Ulm, Germany, to see my brother who had found
a job in Germany. I spent the night at my brother s apartment and the day after I left to
drive all the way to Leiden. I got to Leiden in the early afternoon on a sunny Saturday,
and I stopped my car next to the open market, along a canal. I grabbed a fish sandwich
from a vendor, and to me it was like, "Woo! This is incredible." Everything was new
the atmosphere, the architecture, the colors, the flowers, the fish, the canals. It was the
beginning of an incredible adventure. There was only one big problem my English was
lousy. I never studied English in school.
Hughes: And neither did you speak Dutch.
Crea: No Dutch. I had learned my broken English out of books the last year in Pavia. I had
literally written on a piece of paper my introductory speech for Professor Van Boom, and
I remember when I first showed up at the Gorlaeus Laboratory in Leiden, I had a piece of
paper in my hand. I had written my few sentences like, "Professor, thank you very much.
My name is I am happy to be here." Professor Van Boom was a young guy, in his early
forties, with a lot of energy and enthusiasm. He had just come back from England where
he had learned this new chemistry, called phospotriester method, in Professor Colin
12
Reese s laboratory, at Kings College in London chemistry that was being applied to
work in DNA synthesis. Jack was setting up his own group in Leiden. He must been
positively affected by my naivete, because he said, "Okay, that s good. Tomorrow I ll
ask one of my Ph.D. students to take you through the research we are doing here in my
lab." I was happy that I had survived that first meeting.
The day after I had one of the most interesting experiences in my career. I got together
with one of the students, Peter Van Deursen, who was doing the Ph.D. thesis in Dr. Van
Boom s laboratory. We sat down in a little room, and he said to me, "Roberto, let s start
from the beginning." I said, "Okay, Peter, go ahead." He said, "Well, first of all, you
have to know that carbon can form four bonds with other atoms." It was like, "Wait,
Peter. I might speak bad English, but I have five-plus years in chemistry. We don t have
to go that far back!" That fortunately lasted only a few days, then I started working in the
lab and establishing myself. By the second year, I was totally doing my things and I was
also coming up with my ideas. The first year was more focused on executing the plan
that Professor Campagnari and I had put together, and I was pretty successful in doing
that.
Hughes: That was to make the enzymes?
Crea: No, that was to create some substrates for the DNA enzymes.
Hughes: DNA substrates?
Crea: DNA substrates. So, the first work was to create a poly-dT [deoxythymidine] attached to
cellulose, because the poly-dT would have been used as a substrate for isolation of
messenger RNA or to create some junction between DNA strands for the characterization
of ligases, enzymes that fill gaps. That was my first work, and I think that was the first
time that I used the cellulose to immobilize DNA.
Hughes: Was the lab using it?
Crea: No, they weren t using it. I was linking chemically-activated mononucleotides to the
cellulose, and then I would add more dT for making dimers and trimers. So the work
involved making chemically synthesized dimers and trimers on a solid support with a dT,
which was the easiest way, because dT doesn t involve blocking-the-moleeule for
possible side reactions. Once I attached those molecules to the cellulose, I had to
quantitate the amount of dT immobilized on cellulose, and then use that derivatized
cellulose to link other DNA substrates by hybridization and enzymatic ligation.
Hughes: Were other people in the laboratory doing similar work?
Crea: No. I was the only one, and in a way I enjoyed working in my own field. But I was
learning from other people how to synthesize small pieces of DNA.
Hughes: Who else were there?
Crea: There were at least another dozen people. Three senior students, Peter Burgers, Peter
Van Deursen, and Jan de Roy were getting ready to get their Ph.D. degree. They were
working on their theses and were bright people. Dr. Burgers ended up working in
13
biochemistry at Washington University, St. Louis. He is a well-established scientist.
Peter Van Deursen ended up working for a large chemical company in Holland. Then
there was a technician, Gary, a lady, working for Jack Van Boom. Jack was working at
the bench himself, on and off, because he was teaching courses in organic chemistry.
Then we had students who would do practice in the laboratory and help us in building
basic molecules or some reagents.
Hughes: Wasn t Herb Heyneker somehow associated?
Crea: No. Herb Heyneker was working in a similar laboratory, but in molecular biology at the
Silvius Laboratory. Mine was the organic chemistry department. I joined the organic
chemistry group at the Gorlaeus Laboratory.
Hughes: Did you mix much with other units?
Crea: No. We were working on the fifth floor of the Gorlaeus, and Van Boom s group was
mainly involved in DNA chemistry, although they were also doing some peptide
chemistry, as well. When I got there, that was it a dozen people in the lab and Jack
himself, and we were cooking and cranking new molecules. So, after the first year, I
submitted my technical report to the EMBO commission and they gave me another year.
The second year I was in Leiden, I continued working on the project of Professor
Campagnari. I remember also I traveled to Ispra to give an oral report on what I was
doing in Holland. I also gave a little seminar on the phospotriester chemistry, and then I
came back to Holland to work on more challenging projects.
I got involved in one project where we were trying to add phosphate moities on the
nucleosides, because the nucleotide di- and triphosphates would allow enzymes to use the
molecules, in this case called nucleotide di- and triphoshate, to assemble along other
molecules. Adding phosphate to nucleosides was important, because most of the energy
in the cell is represented by ATP. ATP is adenosine triphosphate. So, the ability to
chemically synthesize this energy-rich substrate would have given us a model to play
with the enzymes and understand their mechanisms. To succeed in this project I had to
find the perfect system to attach phosphates to the nucleoside. In other words, I would
start with a naked nucleoside or protected nucleoside, depending upon which are the four
bases I would use as substrate, and then I would add a phosphorylating agent to attach a
first phosphate to the five-prime end of sugar, and then use that use that phosphate as a
target for further addition of one or two more phosphates.
To make a long story short, my first publications in Holland relate to two areas. One is
the synthesis of small DNA molecules, and the second one is the synthesis of
monophosphate, diphosphate, and triphosphate via an active intermediate. This
experience turned out to be very important for my contribution to gene synthesis at City
of Hope and Genentech, in California, and we ll get to that. So, as you see here [indicates
bibliography], my contribution in Leiden led to a paper which was submitted in 1975 by
Professor Van Boom and myself as the second author. The title tells you that we were
taking a single nucleoside and turning it into mono-, di-, and triphosphate.
In the meantime, Dr. Van Boom was gaining a reputation. He was getting on the
international radar screen as one of the most creative and innovative chemists, and of
course his group as well. He had a feature article in a chemistry magazine in Holland
14
where people were talking about DNA and RNA synthesis and the possibility of creating
genes as well. In reality, we were working with small synthetic molecules called
oligonucleotides. In the meantime, Jack s group had published another paper where we
describe the synthesis of an oligonucleotide of seven units, via the chemical coupling of
one nucleoside to the next and to the next and so on. There was no doubt in my mind that
Jack Van Boom was one of the most creative leaders in oligonucleotide synthesis, and his
reputation was gradually increasing due to the quality of his publications and the
development of new methods.
Hughes: Were you urged to publish as soon as possible? Was there pressure?
Crea: Yes. Keep in mind that Professor Van Boom published, on average, between ten to
fifteen papers a year. That was a lot for 1975. I managed to get two publications in 1975,
and a lot of work wasn t published because the EMBO fellowship ended at the end of
1975. Jack managed to convince the University of Leiden to keep me in his lab as an
associate professor. The university gave me a contract, through the ZWO research
organization, to stay at the university as an employee, as an associate professor, to
continue the work on DNA. They were paying me quite a bit of money for that time and I
was supposed to do research for the benefit of the university. As the grant from the
European Community expired, this new contract by the University of Leiden kicked in,
so I had a third year to look forward, which was now 1976.
I enjoyed working as an associate professor in Jack Van Boom s laboratory. My duties
were limited to do research in the area of DNA chemistry.
Hughes: Most people start out as an assistant professor. How had Van Boom managed to finesse
Crea: Because I had already a Doctoral degree in chemistry from Pavia University, I first
worked as assistant professor when I got the grant from the European community. So the
fact that I had two years of assistant professor experience qualified me to be hired as an
associate professor by the University of Leiden.
I enjoyed the period in Holland very much. For me, it represented almost a brainwash in
terms of attitude toward research and freedom to be creative, freedom to express yourself,
and for the quality of scientific research. Holland, with respect to Italy, was like day and
night.
Hughes: Explain a little more, what the day and night was.
Crea: Well, in Italy, with all the financial constraint of a public university, you had very much a
specific set of laboratory operations to do. You would be given some kind of assignment
by your supervisor, but most of the time this meant the reproduction of other people s
data. Somebody in the United States or England had published a paper with some
intriguing results. If the Italian scientists wanted to learn more, they would try to
reproduce that research in the lab. There was very little or no creativity or originality, at
least for young scientists. For me, it was difficult to get excited about it. In addition,
there was an overlaying philosophy in research which basically was "You wait until it is
your turn. No matter how good you are, don t forget there are other people ahead of you
in gaining job stability." Everything is so precarious in Italy that to get a job at the
university, you have to wait six years, ten years. I was in an environment in Pavia where
15
first of all there were other people before me. Second, there were college graduates with
a college pedigree and much more prestigious academic credentials. I was in line for
what and how long? For becoming an associate professor with no real autonomy, with no
freedom to pursue your own ideas. I was very happy to leave that environment, which
was depressing in many aspects because there was no future for young scientists.
Hughes: Were you very aware of it in Italy, or did it take going to Leiden ?
Crea: No, I was not aware of it when I went to Pavia. Once I start realizing the uncertainty of
the academic career in Italy, I got interested in doing something different. I didn t want
to pursue an academic career, politics never appealed to me. I wanted to really leam how
good research gets done. I think the experience of Prof. Campagnari in the U.S. and my
experience in Holland made an incredible impact upon myself, because I saw the truth.
##
Crea: In Leiden we were exploring, in effect, uncharted territory. What is fascinating and
exciting in research is knowing that the work you are doing is done for the first time and
that you can find new things that nobody has discovered before, and that you can leam
some new concepts and new mechanisms. In the field of DNA chemistry, we all knew
that Van Boom s lab was one of the world leaders, and that the better we were
performing, the better chance we had to get recognized in the international arena. And
then the environment was beautiful: first-class laboratory, modem building, modem
equipment, no major constraints on purchasing chemicals, and reagents. In Holland, for
instance, I was one of the few people in the world with the chance to learn to use an
HPLC [high performance liquid chromatographer] for the purification of synthetic DNA.
That also became very important when I joined City of Hope and Genentech. I was
experimenting with a piece of sophisticated equipment which was a sort of prototype in
the scientific world. I was gaining early experience in an area which turned to be very
important for the gene synthesis from synthetic DNA fragments.
Hughes: How much interchange were you having with Van Boom?
Crea: A lot. I was working in the same laboratory where Professor Van Boom had his desk, and
I had my bench space just across his desk. It was a wing of a laboratory floor, with one
small lab in one comer connected to one big lab, and then a few more labs across the
corridor. I was in the small lab together with Jack Van Boom and his assistant, so I had a
chance to interact a lot with him, on a scientific and personal basis. We became good
friends. Today, we are friendlier than ever, because of the many shared past experiences.
Of course we have mutual respect for the things that we have done in our career. Our
friendship goes back to the first two years I spent in Holland. He had a young daughter,
Stella and a lovely wife, Lisbeth [Bep], and I was spending time with Jack s family a day
or two every week at his place. When I was in the lab, I leveraged on my cooking skills
and my Italian heritage to gain acceptance in the laboratory. So from time to time, I
would give Italian parties in my apartment, full of pasta and meatballs, and everybody
would come and go crazy on food, because in Holland the local cuisine is not the forte of
that country.
It was a very enjoyable academic environment. I was playing soccer during the lunch
break with other colleagues. I was one of the few Italians in a university building with
16
more than a few hundred people. Little by little, I felt very comfortable, because the
environment was so friendly.
Hughes: Was your English improving?
Crea: Oh yes. Of course, I was practicing my English every day in the lab. I was learning from
television, radio. I even attempted to learn Dutch, but it was too overwhelming. Dutch
has strange sounds that are not very compatible with Italian.
Hughes: Was English the language of the laboratory?
Crea: English and Dutch. It was almost fifty-fifty. I wouldn t understand the Dutch entirely,
but I learned how to understand the most important things. English was my way to
express myself and to communicate with other people. In Holland, English is the second
language. Also, I found some nice people in the academic environment who loved Italy
and were speaking Italian. Also, I met other Italian scientists in other departments of the
university. Holland is a very open country, very liberal. Leiden University is one of the
most prestigious, the university where Einstein taught physics for a few years, and is the
first non-Catholic university in Europe. It s very liberal. They had also an Italian
literature faculty, so I had friends there.
After three and a half years in Leiden, I was ready to leave, though, for many reasons.
One, the contract with the university had expired. It was a two-year appointment, and at
the beginning of 1977 1 found myself living on social security. Financially, it wasn t bad
at all because I was receiving eighty percent of my salary, but that wasn t a permanent
solution. I had no chance to go back to Italy either because nobody in Italy was working
in that area of synthetic DNA research, [tape interruption]
I was ready to go, because it was difficult to find a permanent job, especially for an Italian
at the University of Leiden with my language limitation. But I was also getting a little bit
tired of routine; things were looking kind of the same year after year. Holland is a small
country, and after a while you can almost anticipate what s going to happen the next
week and the next month. During my free time, I enjoyed very much visiting museums, a
lot of art, music. I think those were very important years for opening my intellectual,
scientific horizons and also socially and culturally.
One of the people I met in Leiden was Professor Arthur Rosch. Professor Rosch was a
very important professor at the University of Leiden. He also was Herb Heyneker s boss.
Professor Rosch knew Professor Campagnari very well. I must say Professor Rosch and
his wife helped me quite a bit in the early time while I was in Holland, because Professor
Rosch s wife, Thrus, spoke Italian. She was very nice in showing me around, helping me
to find an apartment.
Professor Rosch was a very influential person in the University of Leiden in that he was
the head of the molecular biology program. So through Professor Rosch, I met Herb
Heyneker, and I learned more about Rosch s activity and Herb s work. I was still
working in Leiden when Herb Heyneker moved to the United States to work with Herb
Boyer. That connection was very important, because when Robert A. Swanson and
Keiichi Itakura decided to recruit someone from Jack Van Boom s laboratory, they asked
Professor Rosch and Herb Heyneker to check me out. It was Professor Rosch who, in
17
response to the due diligence request, wrote to Herb that I was the chemist with golden
hands. That was my reputation in the chemistry department of Leiden University. I still
keep a copy of his letter, so everything I am saying has a nice piece of written testimony
that we can use to double check everything.
In the summer of 1976, Jack Van Boom got a letter from Dr. Itakura, indicating that there
were postdoc openings in his lab. Professor Van Boom asked both Peter Burgers, who in
the meantime had finished his Ph.D., and myself whether we were interested in going to
California. I remember Peter Burgers rejected the offer, thank God!, to come to work for
Itakura and Genentech.
Hughes: Do you know why?
Crea: It think he was little bit more conservative. He knew that as a Dutch scientist with a
Ph.D. degree, he could have found easily himself a job in Europe or in Holland. So, he
had more chances to get other jobs and he decided to step back and see what other offers
were coming his way.
The letter from City of Hope and Genentech was pretty vague. Nobody knew of
Genentech. Nobody in Jack s lab knew of City of Hope. Of course we knew of Dr.
Itakura as one of the chemists involved in the synthesis of DNA from his publications
while working in Canada. Professor Van Boom s reaction was, "Well, if you re
interested, I m going to write a letter to Bob Swanson, asking him to pay for a trip,
because I want to go see for myself what s going on there." So, it was a way for Van
Boom that he wouldn t miss anything new. But at the same time, it was to reassure me
that I was going to work for a decent organization. Jack Van Boom traveled to San
Francisco where he met Swanson. Then, Bob and Jack traveled together to City of Hope
where they met Keiichi Itakura. Jack, after he returned to Leiden, told me of this trip and
of his discussion with both Dr. Itakura and Bob Swanson on gene synthesis and the
cloning strategy with synthetic DNA for production of proteins in bacteria. So, for me,
after being reassured by Jack on the novelty and importance of the project, it was like,
"Okay, now let s get ready for the big jump." After back-and-forth correspondence with
Keiichi Itakura and Swanson, we finally decided that the best for me would be to join the
City of Hope group under the Professor Itakura s leadership, starting in May 1, 1977.
So, that was, for me, the conclusion of an important experience in Holland and the
beginning of a new one in the United States. I had no idea what was on the other side of
the Atlantic. It was just too taken by this excitement to fulfill a dream of mine to work in
the United States, especially in California. A young scientist, a European scientist, thinks
of California as the dream country for many things, including research. I literally packed
everything in two suitcases because I couldn t afford to bring anything else with me. I
gave my furniture away to friends and put some in storage and, of course, I forgot
everything about it. I left the Netherlands with two suitcases, an overcoat, and a brand-
new camera.
May 1, 1 flew from Amsterdam to Los Angeles on a Boeing 747. It was pouring rain in
Holland, and when I got Los Angeles, it was like ninety-five degrees. I was carrying my
suitcase with my coat on, and people were looking at me as if I was crazy. My first
impression of the United States and California sunny sky, exotic palms, hot weather,
the Lakers playing end of season games, the buses were striking, and I had to go from the
Robert Swanson and Roberto Crea photo courtesy of Roberto Crea
Keiichi Itakura, Arthur Riggs, Roberto Crea, and Tadaaki Hirose (1 to r), City of Hope, 1977
The laboratory at City of Hope in which the DNA synthesis for the somatostatin project was
performed. Photos courtesy of Roberto Crea
19
[Interview 2: July 19, 2002] ##
Hughes: Dr. Crea, last time we brought you up to your arrival at City of Hope, so I think we should
start today with your impressions.
Crea: The day of my arrival, I really didn t have any idea of what to expect in terms of work
plan. I knew how to recognize Dr. Keiichi Itakura because I had a picture of him with me,
but I never met him before. I didn t know much about City of Hope Medical Center
either, other than that it was a major research center and a medical institution dedicated to
treat patients with terminal disease, so from a scientific point of view, really it was kind
of the beginning of a discovery process for me.
I asked the cab driver to drive me from the airport, Los Angeles International, to the City
of Hope, and the reaction of the cab driver was, "It s far away." I said, "Well, I have to be
there because tomorrow morning I start working, so take me anyhow." That cab ride cost
me a fortune. It was almost a hundred dollars. But in any event, I got to the City of Hope
at about 9:30 p.m. It was already dark, and I managed to get some information from a
lady at the reception, and they were expecting me. She indicated that I would stay in one
of the little houses they had on the campus, an area called Rosenkrantz Campus which
had small apartment complexes for guests, just a room and a bathroom. I was happy to get
into my room and crash after a long trip.
I remember in the morning I had an early appointment. Dr. Itakura was coming to pick
me up at the apartment at the Rosenkrantz. I was ready for him with my blue jacket and
tie. Suddenly I saw a fellow walking from the other side of the building in jeans and a
striped tee-shirt, youngish looking, and I didn t know who it was. He came to me and
said, "Hi, I m Professor Itakura. Nice to meet you." So that was the first shock. I was
expecting a more formal Japanese professor. But here was this guy my age probably,
dark hair, young looking, taking me to the laboratory.
Hughes: And speaking good English?
Crea: Speaking decent English, which made me feel better because obviously I was a little bit
afraid of being able to communicate with my Dutch English. But that wasn t a problem.
The first day I remember he took me to the laboratory, and that was kind of a surprise,
too, because the laboratory was really a small one. It was a wing of the City of Hope
Hospital. In essence, there were two rooms, plus a little office. The rooms were set up to
accommodate a chemistry laboratory, with fume hoods and benches. But it wasn t more
than a thousand square feet of lab space, so fairly small. I didn t dislike the idea of a small
lab because the whole thing had the feeling of a totally new adventure. I had left a big
building in Netherlands, seven floors, all laboratories, with all kind of sophisticated
equipment. I was joining a California group, and it was all new and all exciting.
One of the first things that Dr. Itakura showed me was like a box, sitting on top of a table.
"You see, we just bought an HPLC, and that s your baby. We were waiting for you
because we understand you have experience with this kind of instrumentation." Then, the
first day, he introduced me to some of the scientists very few. There was one more
Japanese postdoc, Dr. Tadaaki Hirose, and there was another Chinese fellow, a Chinese
20
lady, and a Filipino technician. That was about the size of the team. Then on and off a
couple of girls came to the lab to wash the glassware.
He showed me the bench, and we spent some time going through the chemistry, the
problems, the challenge. Dr. Itakura went on to explain what he was trying to do, the
relationship with Genentech, the relationship with Bob Swanson and Herb Boyer, et
cetera. It was great because not even twenty-four hours since I arrived in California, I was
already comfortable in my scientific territory. I had my white coat, and I was ready to go.
Hughes: Now, had you heard about the arrangement with Genentech, before you arrived?
Crea: No, not really, and if I did, I wasn t paying too much attention. My perception before and
after my arrival was that Genentech was sponsoring research at City of Hope, and
essentially everything that we were going to do was in support of this collaboration
between City of Hope and Genentech. All the chemicals, all the equipment, all the
consumables, including my salary and other people s salaries, in the Keiichi Itakura
laboratory were paid by Genentech. My understanding, which was confirmed later on by
the hospital administration, was that I was to be employed by City of Hope as a City of
Hope postdoctoral fellow, but in reality my salary with many other things was coming
from a grant from Genentech.
Hughes: Had you heard about recombinant DNA? Was the name Herb Boyer familiar before you
arrived?
Crea: Yes. Although I never met Herb Boyer before, he was just a big name in my mind, a big
professor. I had seen some of his publications. I didn t understand well his research,
because his field was totally different from what I had been trained. But I understood that
the collaboration between the two organizations involved the City of Hope team to
synthesize genes for mammalian proteins. Those genes were going to be used by the
molecular biologists up in San Francisco and by Boyer s group at UCSF to create copies
through the new techniques of plasmid cloning, and eventually to use the gene as a
blueprint for production of proteins in bacteria. It was all new to me. Recombinant DNA
had progressed in the U.S. to the point where things were happening almost on a daily
basis. My focus, when I joined the Genentech team, was entirely on the chemistry. The
big challenge was to synthesize oligonucleotides that could be used for the assembly of a
synthetic gene.
Hughes: The somatostatin experiment had started.
Crea: Yes, absolutely. What I was told by Dr. Itakura when I arrived was that they were
working at City of Hope to synthesize the gene for a fourteen-amino-acid mammalian
protein called somatostatin. But things were slow because one or more of the fragments
necessary for the assembly of the gene weren t working very well. There was a chance
that we had to re-synthesize some of these fragments. They were also hoping that my
experience in the purification of oligonucleotides by HPLC would be of help.
Hughes: Was your experience with HPLC one of the reasons that you were attractive to Itakura?
Crea: Well, I never asked him, to be honest, but I underst9od from day one that he was aware
that I had experience with HPLC. A few years later, when I spoke to Professor Van Boom
21
about this issue, he confirmed that during his visit to Genentech and City of Hope, and
during the phone discussion he had earlier with Swanson and Itakura, the issue of the
purification of oligonucleotides was very important to Genentech because they were
having problems isolating the pure material with traditional methods. They were indeed
looking forward to purchasing an HPLC, upon my Dutch boss s recommendation, as a
means to solve the problem.
Hughes: What did you immediately set about doing?
Crea: I remember the first couple of weeks were pretty intense because on one side I was
working on putting up HPLC, setting up purification. On the other side, I was acquainting
myself with the chemistry Itakura s people were using for the DNA synthesis. At the
same time, I was developing new ideas on how to solve some of the problems that I saw
immediately in the laboratory as some limitation in the oligonucleotide chemistry. It is
fair to say that I was the most experienced DNA chemist in the group, with the exception
perhaps of Dr. Itakura, who was dividing his time between managing the administrative
aspect of his laboratory and active participation in the laboratory work itself. Dr. Itakura,
in my mind, from day one was supervising the group, administering the relationship with
Genentech, and overseeing the technical operation and progress generated by four or five
people in the lab.
Hughes: So, he wasn t at the bench at all?
Crea: Honestly, I saw him often coming in and out, checking, monitoring, discussing with
scientists, then going back to his office. I understand now the challenge: I think as a
manager of a scientific team, probably, he was more involved in administration and
overall direction and success, and he didn t have the time or didn t have the desire to be a
bench chemist any longer.
Hughes: Did that surprise you?
Crea: No, it didn t surprise me because I already saw this kind of managerial challenge in the
Netherlands. My former boss, Professor Van Boom, although a fantastic bench chemist,
as his group became bigger he had also some teaching obligations he wasn t spending
time at the bench in the laboratory any longer. He wanted to do it. He is a very talented
chemist, and he was doing from time to time his own experiments. But not anything with
continuity, which is necessary because it is difficult to start experiments and then walk
away because of other obligations.
For me at City of Hope it was different: up in the morning, go to the lab, put on my white
coat and start working from eight o clock to six o clock, seven o clock in the evening.
That was my life, trying to enjoy the work in the laboratory produce, perform, invent,
develop, deliver. So, I was a good fit for Keiichi Itakura in a way, because he started
relying upon my experience to run his group. I was the second in command, and soon I
became responsible for the laboratory operations. Because of my past experience in Van
Boom s lab, I was able to make immediate contributions to the Genentech-City of Hope s
effort, to the point that only a few months after I arrived, I was considered an important
contributor to the somatostatin project. That was very exciting and rewarding for me,
because, although the somatostatin project started and was going on prior to my arrival, I
was able to jump in and become a contributor and a good one with the introduction of
22
the new techniques, both as related to the synthesis as well as the purification of
oligonucleotides.
Hughes: Itakura, from what I understand, is known for the triester approach. Is that indeed what he
was using when you arrived?
Crea: Yes.
Hughes: How did that jibe with what you were doing in Leiden?
Crea: Itakura came to City of Hope from the laboratory of Professor Saran Narang, in Canada,
who is one of the few pioneers of the phosphotriester method. So Itakura was doing
phosphotriester chemistry at City of Hope. Phosphotriester is a general denomination of a
chemistry which is used to build long sequences from individual nucleosides. So the units
need to be assembled into a string, and the way you could assemble at that time, was
either by phosphodiester or phosphotriester. The phosphotriester was the new method,
developed originally in England by Professor Reese and Professor Van Boom.
In the United States and North America, there were a few laboratories active in this area.
There was a lab run by Professor Robert Letsinger, for instance, in Chicago at
Northwestern University and a lab run by Professor Narang in Canada. So, at that time,
less than a dozen laboratories all over the world were developing this new technique.
Phosphotriester means that you fuse one nucleoside to the next, via a chemical
condensation step which gives you a neutral molecule. The phosophate, which is
necessary for the link between two nucleosides, is fully protected. That allows you to
work up the resulting molecule, the synthetic product, in a much easier environment,
which is organic solvents rather than going through water-based purification with the
phosphodiester method, which is the technique that was perfected by Professor Gobind
Khorana at MIT. The phosphotriester method turned out to be much more efficient, much
more clean and elegant. It was clear, however, that there was a lot of work to be done to
optimize a new chemistry to the point that one can control and scale up the single steps
involved in the phosphotriester to be able to synthesize DNA fragments for the assembly
of long genes.
That was exactly what we did in the Netherlands. I and my colleagues in Leiden worked
for a number of years, trying to optimize the synthesis of small molecules into bigger
ones. One of the key chemicals to accomplish a good synthesis with nucleosides is this
condensing agent called phosphochloridate. In Leiden I worked with the
phosphochloridate coupling agent using a lot of combinations between different chemical
groups. So, when I arrived at City of Hope and I learned the special combination that
Keiichi Itakura was using for the synthesis. I immediately combined what I knew from
my Dutch experience with what Keiichi Itakura had put in place at the City of Hope. By
doing that, I developed a very important chemical reagent which made the synthesis of
dimers and trimers very efficient and simple. This chemical, which is called 2-cyanoethyl
2,4dichlorophenyl phospochloridate, turned out to be the object of a patent application by
Genentech in 1978. 1 believe that was really an important development because it became
much faster and much easier to produce a very large quantity of building block
molecules, dimers and trimers, which you could now mass produce, purify, and store
them in the refrigerator for multiple use. Then, when we needed to build a DNA chain of
fifteen nucleosides, it became easy to do it from the appropriate dimers and trimers. We
23
were the first to develop the concept of a library of building blocks because it became
much easier to make those building blocks with the chemical modification that I
introduced.
Hughes: Did you make that modification quickly after your arrival?
Crea: I probably did after a couple of weeks, because the synthesis and the coupling
phospochloridate used by Dr. Itakura s laboratory wasn t effective enough. As the
chemical coupling was very much incomplete so the yields weren t high. But more than
anything else it was difficult to purify the end product from the starting units.
Hughes: I heard about an episode where Swanson came down, expecting the experiment to work,
and it didn t.
Crea: I think I can provide some insight to your statement. There were some problems
concerning the purity of the DNA oligonucleotides, which I believe we solved very
quickly by using the HPLC. I think that for the somatostatin project we only used seven
or eight DNA fragments, but I remember that there was one fragment in particular that
was giving problems during the assembly of the gene. I think it was fifteen bases long.
Hughes: This was before you arrived?
Crea: Yes.
Hughes: Did the problem continue?
Crea: After I arrived we re-did the synthesis and purification by HPLC and that immediately
worked. So the somatostatin gene was reassembled with this new cleaned-up fragment
and used for the recombinant DNA experiment. Now, what you are referring to is the fact
that the first time we tried to express somatostatin in E.coli, we didn t see or detect any
protein, and that was a big headache. I remember a meeting where we all convened to
discuss the problem.
Hughes: Was Swanson present?
Crea: Yes, and Boyer together with Drs. Heyneker, Bolivar, Riggs, Itakura, and myself.
Ultimately, out of that meeting an important discovery was conceived, which is the
strategy of producing a small protein as a fusion protein in bacteria. In our case, this
strategy consisted of putting the little gene for somatostatin (14 amino acids) behind the
beta-galactosidase gene of E. coli (a much larger protein), and putting between the two
genes a codon which in the bacterial cell produces an amino acid, methionine, which
ultimately can be cleaved at the end of the process by treatment with a chemical called
cyanogen bromide to release the somatostatin from its large, stable precursor. That, as far
as I remember, was a contribution which was ultimately attributed to Professor Riggs. It
was an interesting meeting because, as I remember, that was the first time the whole
group convened at City of Hope it must have been in the summer of 1977 to discuss
the project and the experimental results. It was the first time I met Professor Boyer and
Dr. Francisco Bolivar.
Hughes: It was the first time that you met Swanson?
24
Crea: Yes, it was probably the first time that I met Swanson. I remember that I had a brand-new
camera from Holland, and I started taking pictures of the scientists walking through the
laboratory and later discussing research results in the conference room. I think that in
retrospect I took some of the first pictures testifying to the birth of biotechnology.
In retrospect, we had a year of extremely exciting events. We started with the failure to
detect somatostatin as a product of the first recombinant DNA expression experiment.
We came up with a scientific strategy that ultimately worked. And that led to the big
announcement to the world that for the first time a peptide of mammalian nature, in this
case a sheep protein, had been produced by bacteria. That was the first time Genentech
and City of Hope sent out a big announcement via a press conference in Los Angeles, and
I was a part of that together with Swanson, Boyer, Itakura, and Riggs.
Hughes: This is the first time I heard it was a sheep gene. I thought it was human.
Crea: No, we didn t have the human sequence; we had the sequence of a sheep protein.
Hughes: Which came from where?
Crea: From San Diego, from Dr. Vale.
Hughes: Oh, I wondered what his part was Wiley Vale.
Crea: Wiley Vale was working on somatostatin. So the peptide was a sheep somatostatin, and
we designed the gene. It wasn t a human. Insulin was the first human gene we used. So,
for me, 1977 was like magic. I came from Europe to do my work. I can provide the DNA
pieces. Other people will put together the pieces into genes and do the rest. I was happy to
be a player, at that point.
Hughes: What was Hirose doing?
##
Crea: He was doing similar chemistry, but the difference with Tadaaki Hirose was that he did
not have any training in DNA chemistry. He was in Keiichi s laboratory for a postdoc
experience. He came from Japan just to leam the synthetic DNA techniques. He was
working at the bench doing in essence what Dr. Itakura would tell him to do, and then as
we develop the new chemistry of coupling, he was involved in the synthesis of dimers
and trimers using my improvements. He is a good chemist and a good, warm, intelligent
person. He did not mind producing the building blocks and then assembling
oligonucleotides a very productive individual, very quiet, nice person.
Hughes: He spoke English?
Crea: He spoke broken English as many other foreign scientists.
Hughes: Tell me how the procedure went. Once you had synthesized the fragments, then what
happened?
25
Crea: The first period at the City of Hope was taken by the somatostatin project as the major
technical and scientific goal. That goal was meant to validate and satisfy the vision of
Genentech s Boyer and Swanson. It was a goal for the City of Hope labs to establish
ourselves as major partners of Genentech. It was a goal that turned out to be extremely
important for the entire industry, because with the announcement of a successful
expression of somatostatin, the world started taking notice that a bunch of scientists in
San Francisco and City of Hope had done, for the first time, this kind of experiment.
I remember that it was a big event! We had a press conference at the Biltmore Hotel in
downtown Los Angeles. In front of the press Robert Swanson and Herb Boyer announced
to the world this event. I remember that the news was picked up by the media as a major
scientific breakthrough. Also, at the same time, we heard that there was a testimony of the
President of the National Academy of Sciences, Dr. Handler, before a recombinant DNA
subcommission of the U.S. Senate which supported this event. Indeed, Dr. Phil Handler
testified that this experiment was "a scientific triumph of the first order." It was maybe to
my surprise, because I wasn t fully aware of what was going on the thing was becoming
bigger and bigger by the day.
From my standpoint, after the somatostatin fragments got out of the laboratory at City of
Hope and became a project for the molecular biologists at UCSF, we were focused again
on improving the synthetic chemistry. Out of that effort, which I can say that I led, we
published two important papers describing the new chemistry to make the building blocks
and the second describes the use of building blocks to make long DNA oligonucleotides.
I also remember two episodes. The first was the celebration with Bob Swanson in
Pasadena. Pasadena has very good restaurants so we decided to spend an evening in
celebration and to discuss future projects. I remember that after the somatostatin success,
every time Swanson was coming to City of Hope, there was reason for celebration. I
remember the celebration at this Italian restaurant. During that dinner, Bob raised the
issue of the next project for the City of Hope group, specifically Itakura s group. We
started talking about human insulin. I told this story to the writer who wrote the book
Hughes: Stephen Hall. l
Crea: Yes, as I remember in that book, Swanson, very pleased with the progress that we had
made in the laboratory, looked at me and said, "Roberto, how long will it take to make
insulin gene?" After some brief moments of silence across the table and after thinking
about the size of that first little gene, I said, "Bob, with the chemistry that we are using
right now, it shouldn t take more than six months." I remember that answer didn t create
a lot of enthusiasm on Itakura s face who said, "It s going to take a lot more than that."
Bob looked at me and said, "If you think that you can do it, you should go ahead and do
it." That was probably the go-ahead for the group at City of Hope to start designing the
human insulin gene from scratch! Itakura and I spent several days to develop a strategy to
assemble the two genes that code for the two insulin protein chains, A and B, out of
twenty-five oligonucleotides. necessary for the systematic assembly of independent genes
for B-chain and A-chain. So, from that evening at the restaurant with Swanson, Keiichi
I.Stephen Hall, Invisible Frontiers: The Race to Synthesize a Human Gene, Redmond, WA:
Tempus Books, 1988.
26
and I started drawing up a plan how to subdivide the genes into DNA fragments which
would overlap for stability and be ideal chains, both for the synthesis and for the
enzymatic ligation. Ligation is an enzymatic way to fuse together oligonucleotides that
line up as a double-strand DNA and have gaps between units. So, in the lab we did some
planning on paper, to design first the fragments and the genes and finally we got down to
a sequence consensus and a strategic chain assembly plan, which was approved by
Keiichi Itakura and Swanson. In essence, we had to synthesize a bunch of
oligonucleotides, spanning from eight bases long to fifteen bases long maybe there was
only one seventeen bases long from our library of dimers and trimers.
In order for us to maximize the effort and minimize the time to complete the project, we
took the twenty-five oligonucleotides, and we started breaking them down into blocks.
The idea behind that was, to use dimers and trimers, which we could make very well now
in large quantity with the new chemistry, and try to use the same blocks over and over for
the project. If you do design a trimer block, you have sixty-four possibilites out of four
natural nucleotides and the genetic code. In theory, you have to synthesize all sixty- four
to cover all of the possibilities. But if you avoid making all of them, that translates in
saving time and money. In our plan, we divided the twenty-five fragments in such a way
that you can reuse the same dimer or trimer several times, just because you ve designed a
synthetic strategy that maximizes the occurrence of the same block. Then you don t have
to synthesize sixty-four. We succeeded in that strategy because in the end we had to
synthesize twenty, maybe twenty-five blocks, between dimers and trimers. That was
really a big asset that we had built and stored in the refrigerator, which we then used for
manufacturing the insulin oligonucleotides and many other projects.
Hughes: That strategy was worked out when Swanson came down to City of Hope?
Crea: No, that strategy was out of Swanson s direct influence. It was chemistry. Swanson
never really was involved in such details. He was relying on the fact that we knew what
we were doing.
Hughes: So this strategy was something that you and Itakura worked out?
Crea: Yes, Itakura and I worked out the scheme. I was responsible for managing and executing
the plan. In essence, I was the head chemist in the lab who would create these pieces and
put them together, block by block, until we had all the molecules purified and ready to go.
Hughes: Was this arduous work?
Crea: A couple of things. First of all, it wasn t easy to purify the dimers and trimers in large
(several grams) scale, for a simple reason: to make grams of your final product, you have
to start with a larger amount of building monomer blocks. We were starting from three,
four, five grams of each individual component and then out of the synthesis and
purification, we would generate a couple of grams of dimer and trimer, which in rum
were the building blocks for further oligonucleotide synthesis.
The problem was that we had to do everything manually. I remember I developed a fast
purification of these building blocks, which helped quite a bit, which was based on silica
gel chromatography, on a sintered glass funnel under suction by a water pump. This
method was called, jokingly, a "two-fingers" purification because the amount of silica gel
27
that we would put on the funnel was about two fingers in height. It was sufficient to
remove from the end product the monomer components which didn t react. It worked
very well. That concept was eventually picked up by a manufacturer who developed a
piece of equipment, an HPLC, with silica gel cartridges for the industrial scale
purification of DNA and other molecules. Later on, we purchased one of those pieces of
equipment, which allowed us to do the block purification automatically, by a machine,
but initially it was done by hand. We were using a lot of solvents to the point that we
were taking everything directly from five-gallon cans and pouring it into vessels. It was a
big volume, a big operation. It was time-consuming and tedious because we had to do it
so many times.
At that time, another DNA chemist joined the City of Hope team from Poland. His name
was Adam Kraszewski. Adam was a skilled chemist. He had experience in DNA
chemistry from his laboratory in Poland, headed by Professor Wieverosky. So there were
three Ph.D. s involved in synthesizing the blocks and the fragments for the human insulin
genes. Ultimately, the work was shared equally between the three of us. Adam became
my roommate in Pasadena. We shared an apartment. There were days when we would
go back home, both of us smelling of all the pyridine and other solvents that we had used
during the day, and it was awful because even a hot shower wouldn t take off the awful
smell of the pyridine from your skin.
Hughes: What about your health?
Crea: At that time, we were all expert in chemical laboratory and not paying particular attention
to our health it wasn t that we were not aware of the potential toxicity of some
chemicals I think it was in part because we were working under safe conditions in a lab
with good fume hoods, so most of the solvents were sucked up by the hoods. But in
effect, there was so much excitement in the lab that even occasional episodes of solvent
spills did not bother us. We were cranking, literally, molecule after molecule, in a
frenetic race to get there first and fast. We didn t spare anything. We put our heads
down, and we created a beautiful episode of efficiency and productivity. I remember that
not only we finished the synthesis ahead of time, but that we got the great news that the
A-gene for human insulin had been assembled very easily. This first part of the project
went indeed very, very smoothly. The B-gene, which was a longer gene, was also
assembled from DNA fragments. But we had a problem with just one fragment, and that
problem ultimately slowed down the molecular biologists in San Francisco. But we
didn t know whether it was the fragment or whether it was the gene assembly. In the end,
we resynthesized the fragment and repurifying it. It really was a well-oiled machinery
that we had put in place for a very important scientific challenge to get first to the
completion of synthetic genes for human insulin. That was really all that was in our
mind. The rest of the time, and away from the lab, Adam and I used to play tennis on the
courts of the Caltech, in Pasadena, whenever the L.A. smog wasn t so heavy to mess up
our throats and lungs. We were keeping ourselves good company.
Hughes: So, he became a friend?
Crea: Yes, we became friends. We shared our European heritage and the love for jazz music
besides battling on the tennis court. The first time I took Adam to a supermarket in
Duarte, in Pasadena it was one of the first days after he had arrived in the United
States he was totally shocked. Poland at that time was still under the communist
28
regime, and he was mesmerized by the amount of food that he saw in one place, bottles
and cans and boxes. It was really a cultural shock for him.
Hughes: How had he gotten there?
Crea: Adam was a postdoc fellow who had been recruited by Itakura and Swanson, in a similar
fashion as I was, from a laboratory in Poland, also known for working with the
phosphotriester chemistry. Adam arrived in California three, four months after I did.
Hughes: Was he being paid by Genentech as well?
Crea: Yes. We were both hired as postdocs in the biology department at City of Hope, and we
earned a decent salary. Adam had left his wife and one kid in Poznan and was planning
to return to Poland after one year in California. He wanted to save money for buying a
house in Poland at his return.
Hughes: Did you have an opinion about the chances of success for expressing a mammalian or a
human protein in a bacterium?
Crea: After the somatostatin s successful expression, we were confident that we could produce
A-chain and B-chain individually by the same fusion strategy. There was no reason to
doubt that the same approach used for the expression of somatostatin would eventually
work for A-chain and B-chain. However, the problem with insulin was compounded by
the fact that the two chains, both bigger than somatostatin, had to be put together to form
one molecule through two disulfide bridges. We didn t know whether the reconstitution
in vitro would work. There were experiments published in the literature showing that you
can take insulin, break down the molecule into A-and B-chain and then recombine them
again to form an active molecule, but nobody in our team had any direct experience with
protein chemistry. We had a plan to produce enough fusion protein in the bacteria that
eventually we could isolate the A-chain and the B-chain in milligram quantities and then
do some experiments in vitro to recombine the two chains.
At the same time we were working on the assembly of the genes for A-chain and B-chain,
I remember that we had a back-up strategy just in case we were not going to be successful
with that first strategy. The alternative experiment indeed involved the use of a third
gene for the C-chain as in nature. While the A-chain and B-chain were assembled,
cloned, and expressed by our molecular biologist colleagues, we at City of Hope were
working in the laboratory to create a gene for a mini C-chain. Mini C-chain means that
we didn t want to copy exactly what nature uses, i.e. a C-peptidic chain to fold the A and
B into an active insulin molecule. Because the C-chain was a long peptide, at least as
long as the B-chain, it would have been another major challenge to build a gene for the C-
chain in a short time. So we started thinking of an expedient to reduce the size of the C-
chain to the bare minimum based upon scientific data that by this expedient the two
chains, A and B, could be lined up by the presence of the mini C-chain in between them,
and then folded in a correct fashion. In effect, what we were toying with at City of Hope
was the first experiments of protein engineering. We were trying to come up with a
modified protein which didn t exist in nature. The presence of a mini C-chain could keep
the two chains aligned so that they could form the disulfide bridge. Then, obviously, the
strategy involved a process to remove that mini C-chain to create the native molecule.
29
Hughes: That s indeed what happened?
Crea: Well, we postponed using that strategy because eventually the A- and B-chains were
expressed separately, and ultimately we succeeded in reconstituting the human insulin by
the first strategy. That mini-C experiment was picked up later on at Genentech, in 1979.
Hughes: Stepping back even further than that, you didn t see any fundamental problems with
expressing a human protein in a bacteria?
Crea: At that point, it was clear that the bacteria would not make any dramatic distinction
between a human synthetic gene and a bacterial gene. Let me explain better. When we
designed a gene for human insulin, we selected the codons for the insulin amino acids to
be compatible with bacteria genetic preference. In other words, we didn t try to create a
human gene. We created a synthetic gene with codons which would be very close to the
ones that bacteria would use, but that would ultimately give us the human amino acid
sequence. We tricked the bacteria in that we picked the codons artificially to be an easy
ride through by the bacterial enzymatic repertoire and to maximize the efficiency of gene
transcription and translation (expression).
Hughes: But not very much was expressed.
Crea: Well, the A-chain was expressed
Hughes: Oh, I was thinking of somatostatin.
Crea: When we did the insulin experiment, the A-chain was expressed nicely. I remember that
particularly, because ultimately everything came back to me. After expressing the fusion
protein in the periplasm ofE.coli, the broth containing the cocktail of proteins isolated
from our bacteria was ultimately given to me for HPLC purification of the A-chain. The
same HPLC which I used for the cleanup of the oligonucleotides was eventually used
with a different solvent system to purify the A-chain and B-chain. So I knew that A-
chain wasn t a problem. When they gave me the crude and I ran it through the HPLC, I
saw a nice peak corresponding to native A-chain which we isolated, and we set it apart.
The A-chain was okay!
The problem came with the B-chain, mainly at the expression level, because one of the
fragments of the B gene was not ligating well, so we never got the B gene in good shape.
So, once again, back to the bench for the resynthesis of the infamous oligonucleotide.
But once we did provide the new fragment the B-chain was expressed as fusion protein
as well. Although the B-chain itself was a little bit more difficult to purify by HPLC,
ultimately the two chains were purified and collected in sufficient amount and given back
to the group of Professor Riggs for the in vitro assembly.
Hughes: I was wondering what Riggs s part was.
Crea: Riggs s laboratory was part of the Biology department of City of Hope and played a
substantial role in the Genentech-City of Hope agreement. The lab included several
people with background in biology and molecular biology, but they were doing a lot of
biochemistry as well. Riggs provided directions. His laboratory was involved in the
processing of the fusion protein, purification and characterization of the recombinant
30
somatostatin, and of course they also played a very important role in the assembly and
characterization of human insulin. In particular, there were, I believe, one or two people
in Riggs s laboratory dedicated to support the Genentech experiments.
Hughes: How much were you seeing Dr. Riggs? Was he in and out of the lab?
Crea: Although physically the Biology labs were two or three hundred yards away from our
chemistry lab, we were seeing Dr. Riggs often. During the lunchtime, we used to get
together in the cafeteria to talk about the progress of our experiments. Often we were
getting together for social events. I remember a party at his house and others at Keiichi s
house. Even Professor Susumo Ono, the head of the Biology department, gave a couple
of parties. So we were all getting together quite often to share lab experience, as well as
to socialize outside the working environment.
Hughes: Had the decision been made before you came to use the lac promoter and the beta-gal
gene?
Crea: Yes.
Hughes: Who made that decision?
Crea: I think that was a contribution from Boyer s group. Boyer, together with Paco Bolivar
and Herb Heyneker, were mainly responsible for the design of the plasmids. What
happened as we started using the plasmid system of expression, Dr. Riggs started looking
at the possibility of using restriction enzyme sites, which are often unique breaking
point[s] along the DNA of a gene, to insert the synthetic gene. I remember in the case of
the plasmid that we used, pBR322, it included the lac promotor preceding the beta-
galactosidase gene. In the coding portion of the beta-gal gene, there were two Eco Rl
sites which could be used for inserting our synthetic genes.
##
Crea: Dr. Riggs was looking at the best possible strategy for the cloning and expression of the
synthetic genes and the presence of specific insertion points in the bacterial DNA turned
out to be perfect for our strategy. The reason why the lac operon was selected was also
because it had a convenient promotor for induction of expression, and an EcoRl
restriction enzyme site just immediately after the ribosome binding site, which was very
convenient for cloning the synthetic A- and B-genes.
Hughes: Was that common knowledge?
Crea: Yes, you could get that from the published literature. The beta-gal gene however had one
more feature that turned out to be very useful for small proteins; it was a second
restriction enzyme site at the end of the beta-gal gene, which eventually turned out to be a
better site for the somatostatin, the A-chain and B-chain, in that the resulting large fusion
protein, mainly beta-galactosidase with the end of the protein fused to the target
mammalian protein, avoided the protolytic degradation of the small proteins by E.coli.
Hughes: Genentech contracted with UCSF, Caltech, and City of Hope for somatostatin. What did
Caltech contribute?
31
Crea: Well, I can tell you a nice story about Dr. Richard Scheller [laughs], who is currently the
vice president of Genentech for research. When I arrived at City of Hope, Dr. Scheller
actually at that time he was a student, working for his Ph.D. thesis was working in Dr.
Itakura s laboratory. He was trying to synthesize a palindromic oligonucleoride which in
reality anneals to itself as[a double-strand chain and which contained the DNA sequence
for a restriction enzyme, EcoRl. The reason for that work was to provide a sufficient
amount of DNA to obtain some crystallographic data of the enzyme and the substrate
itself to figure out how and why the EcoRl enzyme interacts with this fragment of DNA,
which as many other restriction enzymes sites, includes DNA palindromic regions. A
palindrome is a symmetric sequence which is recognized by various proteins as a unique
binding and cleavage site. So, that was the work that Mr. Richard Scheller was doing at
the time that I got there. Richard was working at Caltech in Dr. Richardson s lab, and I
think that structure of proteins was their main work , but it was of no consequence for the
experiments that we did on somatostatin and insulin. It was part of the research
conducted at Caltech.
Mr. Scheller managed to get some shares of Genentech early on from Bob Swanson
because of this research at Caltech. The day the South San Francisco company went
public, there was an article in Newsweek magazine, showing the picture of Richard
Scheller happily looking at the fortune he had made by being one of the first stockholders
of Genentech. The title of that article was "Instant Biotech Millionaire." I imagine
neither Richard Scheller nor Bob Swanson had thought that five hundred shares, which
was the number of shares Mr. Scheller had received from Genentech, had become so
valuable as to represent a lot of money.
Hughes: Had you been offered Genentech shares while you were at City of Hope?
Crea: No, when I was at City of Hope, I was not offered shares. I did not even know that such a
thing existed until after I accepted a job with Genentech, and even at that point I was
totally naive, as an effect of coming from a different world. I didn t realize the
importance of shares until late; I accepted the job offer as it was offered to me by Bob
Swanson with a great deal of enthusiasm and no negotiation. I was already satisfied with
having a decent salary, but more than anything else I was very thrilled to have a chance to
staff and direct my own laboratory. The job offer I got from Swanson did not
contemplate the small number of shares which was given to me after I moved to San
Francisco and started the DNA laboratory.
Hughes: But they were not really an incentive? You would have gone without the shares?
Crea: Yes, I would have gone without shares. I remember one episode when we had a dinner
with Tom Perkins, in Long Beach. This time we were celebrating the big success of
human insulin. I was sitting next to Tom Perkins at the table and during dinner I asked
him a simple question, "Tom, what do you do with the shares of Genentech?" "Well, my
suggestion is that you put them in a drawer and you forget about them. One of these days,
you ll find out that they are worth a lot of money." That was very good advice. In
retrospect, I could have negotiated a better deal with Swanson before I joined Genentech.
I have to be very grateful to Dennis Kleid and David Goeddel, who were hired to join
Genentech in South San Francisco, for renegotiating with Swanson on the shares. At the
time I was moving from City of Hope to South San Francisco, they negotiated a deal
32
better than mine. As a result of that agreement, Swanson decided to adjust the number of
shares to be more compatible with those of Dr. Goeddel and Dr. Kleid.
Hughes: Was there ever any questioning of why you would go from what up till then had been a
strictly academic career into industry?
Crea: In my case there was no issue whatsoever because I never felt that the Genentech
environment was different from an academic environment. I must correct myself: Yes,
there was more pressure. Yes, there was more focus, but in the end we were driving a
brand new technology and we were performing brand new work, and generating
discoveries almost every month. So the environment both at City of Hope and at
Genentech was in some extent similar to academia but more exciting in that we could
finally foresee the benefits of what we were doing in the lab. For me personally, I never
felt any pressure in going from Leiden, an academic laboratory, to City of Hope, a
medical institution, and then from City of Hope to Genentech in South San Francisco. I
enjoyed quite a bit of freedom and control at Genentech while developing new things,
and that was very important to me. I didn t mind at all the challenge of exploring
uncharted territories for a private company, such as the one of producing out of
microorganisms useful proteins for medical and business applications. I thought that ours
was first a fantastic scientific challenge; the business implications at that time didn t have
any influence on my scientific decisions. Beside the fact that I wasn t involved in the
business aspects and they were too far in the future to bother about. For me, it was more
building an exciting career in research, a dream come true and I was getting that
opportunity, both at City of Hope and Genentech.
With the success of the company, it became clear that some people started focusing on
this unusual migration of brains from academia to private industry and they did not like it.
They made a big deal out of it, to the point that you could read titles of articles such as:
"Prostitution of brains in professionals by accepting offers by private industry,"
"mercenaries of science," et cetera. Big words, which to me were inappropriate because
in the end it was high-quality research, very much oriented research, and I was perfectly
comfortable with that notion.
Hughes: Did you notice any shift at City of Hope, compared to Leiden? How was City of Hope, in
terms of undirected, basic research? Was it supported? Did it thrive there?
Crea: Well, the profound difference between California and Holland was the strong feeling of a
pioneering work. In Holland, we were structured to do certain things, to publish papers,
to address scientific chemistry problems. The goal in Holland was to produce a very nice
paper, go to symposia or congresses, and let people know who you were and what kind of
work you were doing. It was an academic environment. The prestige was having your
name on a nice paper, which would be appreciated by peers at University. In California it
was more, "Let s go for the big enchilada." [laughter] "Let s build out of the science and
explore some exciting commercial opportunities." The idea of building a company, or an
industry, was at its very beginning . It was clear from what the press was writing about
Genentech that the potential, intrinsic to the technology of recombinant DNA and
biotechnology, was huge. We scientists were kind of naive, young and skeptical in a
way, but we were there; we were at the front of the technology, and we were driving that
technology. The focus was more on getting there first and understanding the potentiality
of our technology and letting Bob Swanson and company s board do the rest.
33
Hughes: Let s go back to the City of Hope and discuss the recombinant DNA controversy which,
when you stepped off the plane at LAX in 1977, was still going on. Had you heard
anything about this controversy before you came to this country?
Crea: Yes, the Asilomar meeting was pretty much picked up by the scientific press. It wasn t
just a local event; it was something that you could read about in Nature or Science. So
the big controversy over recombinant DNA was pretty much live and kicking when I got
to California, but it was something which, honestly, didn t affect my job. I was not
directly involved in dealing with these issues. It wasn t my expertise or my field of
research. It was only an indirect issue or problem that somebody was addressing and that
eventually we would have to cope with, but not to the extent that it would affect my part
of the work. The fact that we were doing chemistry obviously insulated our group from
any concern about microorganisms. But we were not making jokes about complying in
our laboratory with the FDA or NIH rules for recombinant DNA research in that we
didn t have to do anything other than make sure that there was a good laboratory practice.
The debate was perceived by me and I guess by the other components of Itakura s team as
an issue that was discussed among the molecular biologists, an issue which eventually
found a happy ending with the publication of NIH rules. Once we knew the rules, we
were going to play that game.
Hughes: You mentioned Thomas Perkins, who of course was on the board of directors and also
played a prominent role in the early fundraising and direction of the company. How
much was he participating? How often did you see him?
Crea: Tom Perkins was an active board member of Genentech and he was very often visiting
with Swanson in South San Francisco.
Hughes: I should have clarified. I m meaning first at City of Hope when you were still working on
the
Crea: At City of Hope, as I said, we saw him after the successful experiment of human insulin.
Hughes: Was that the first time you had seen him?
Crea: That was my first time. He was the only director outside of Boyer and Swanson, who
came down to City of Hope to share his excitement and gratitude with the scientists. In
my mind he was the mentor, the experienced business guy who would provide Bob
Swanson with sound advice and guidance in building a business organization. I
remember he was also at the open house when we built the laboratory in San Francisco.
He was there together with Mr. Eugene Kleiner, the two VC [venture capital] principals
[of Kleiner Perkins], and from time to time we would see Tom in South San Francisco,
his red Ferrari Testarossa parked outside Genentech. That was the sign that Tom Perkins
was visiting. I remember that he was driving a beautiful Ferrari Testarossa to the labs
wow, that was my dream! We saw that car maybe once a month.
Hughes: What were your impressions of him as a personality?
Crea: Well, Tom Perkins has such a magnetic personality. He s tall, nice looking, elegant. His
presence is something that you notice in the room, but also his intelligence and his soft
speaking. It was a sign of maturity and knowledge. There was a lot of respect for him at
34
Genentech. He was considered by everybody as the most knowledgeable venture capital
investor in the Bay Area. He came also with quite a bit of successful background,
because his name was associated with some of the big successful stories of the Silicon
Valley. Of course the fame preceded him and followed him; we knew he had a beautiful
house, a beautiful wife, a beautiful life. Tom Perkins was like a living legend if I am
successful, that s what I want to be.
Before we move on from city of Hope to Genentech, I want to say that I met Shirlee Fox
at City of Hope, a few months after my arrival. Shirlee was employed in the office of the
administration reporting to the director, Eli King. She was involved in the management
and monitoring of the budget assigned to Itakura s group. We were spending the money
granted by Genentech to City of Hope for the recombinant DNA programs, so one day I
walked into the office of Mr. King with Dr. Itakura and I met Shirlee.
What struck me most out of that first encounter was a mix of beauty and positive energy
coming out of Shirlee s genuine and natural personal interaction with people; I felt
immediately attracted by that spontaneous energy mixed to her exotic natural beauty.
Shirlee was my first black American relationship in California, and it turned out to be the
most important one in my life. In the following months, we had many opportunities at
City of Hope to get to know each other, especially during the lunch breaks, and I believe
that contributed to a great extent to bring us closer. As we learned more about our
families, our past experiences, and common interests in life, we felt closer. It is still
surprising to us how two people apparently so far apart physically and culturally for their
entire lives can find themselves so similar and close to each other when it comes to
family, feelings for their loved ones, and pride of their culture and experiences. I guess
that learning about ourselves and sharing our past experiences contributed greatly to
overcome Shirlee s first impression of me, which later I was told included "being short
and speaking broken English."
m
35
[Interview 3: August 1, 2002] ##
Hughes: What did you find when you arrived at Genentech and what were your impressions of
the company?
Crea: My first formal relationship with Genentech came in the form of an offer letter by
Robert Swanson, and the letter was sent to me sometime in the spring of 1978. Bob, as
president of Genentech, was offering me a job as the director of nucleic acid DNA
chemistry. In effect, he was designating me as leader of the chemistry group in South
San Francisco. I was very pleased, of course, to join formally the company and move to
San Francisco. We were wrapping things up at the City of Hope. We were still working
on a number of projects at that time, even if we had completed the human insulin
project, so I decided together with Bob and Keiichi Itakura to postpone my departure
from City of Hope to the fall of 1978. In essence, I spent the late spring and summer in
this transition mode. I was preparing myself to take the lead and head the effort in San
Francisco, but at the same time I was working at City of Hope to complete other
projects that we were pursuing in collaboration.
My first day at Genentech started in mid-September of 1978. 1 remember that because I
flew from Burbank Airport to look for an apartment in San Francisco. In the meantime,
I was offered by Bob Swanson an accommodation in his apartment in Pacific Heights,
San Francisco. So I spent a couple of days, a weekend, looking around to see if I could
find an apartment for myself. Ultimately, Bob was very nice to offer for rent a room in
his apartment, which had been occupied by Brook Byers. Our understanding was that I
would move soon and take over Brook Byers s room and move my household furniture,
which wasn t much, to Bob s apartment in San Francisco.
When I arrived, Genentech was still organizing itself. In the summer of 1978, together
with Dennis Kleid and David Goeddel, we were in effect designing the laboratories,
providing some sketches how to organize the space in South San Francisco to
accommodate different laboratories. I remember that when I first joined Genentech,
there was construction going on at the facilities, and my laboratory was being put
together with a few rooms and benches. Interestingly enough, the chemistry laboratory
was the largest laboratory at Genentech. So, it was very exciting, because we literally
started from scratch. We designed the different chemistry bays the hoods, the
benches from zero.
Hughes: Was this the first building that at the very start was occupied by other companies as well
as Genentech?
Crea: Yes, this was the very first building, but I don t remember which companies occupied
that building. Genentech had the corner of a long stretch of warehouses, and I remember
we had approximately 10,000 square feet.
Hughes: So the construction that you re talking about was internal.
Crea: I m talking about remodeling an empty warehouse to accommodate laboratories,
offices, conference room. That work was completed sometime in October or November
36
of 1978. 1 still have pictures of that party when we had the first open house at
Genentech, with still a lot of uncompleted furniture. It was an empty laboratory.
I brought from City of Hope one technician, Parkash Jhurani, from Keiichi Itakura s
laboratory, and I hired another one, Mark Yasser, from SRI, Stanford Research
Institute, so I was putting together the embryo of my team, which was going to be about
eight to ten people.
Hughes: So until November or so, you really couldn t do any research?
Crea: No, we were just setting up the chemistry, buying equipment, buying chemicals and
doing the very first experiments, so it was at a very early stage. We were not working on
any major projects. As a matter of fact, in anticipation of completion of the laboratory
and the hiring of people, we were continuing collaboration with City of Hope. Most of
the material that had been used for the human growth hormone and the bovine growth
hormone came from the City of Hope laboratory.
Hughes: Why was that?
Crea: Because there was an urgency in cloning the bovine growth hormone and the human
growth hormone, and the work that the molecular biologists had done led to the
isolation of an incomplete gene. In other words, the gene to be used for the expression
of human growth hormone required some patching. That was one reason we needed
some DNA fragments. But the major reason was that the early experiments with human
growth hormone were not successful. One of the hypotheses which had been discussed
among the scientific staff was that the very beginning of the gene of human growth
hormone had a very rare codon for E. coli because it came from a human sequence. It
could not have been recognized by E. coli and would have been a difficult start for the
synthesis of the protein.
Peter Seeburg, who was in charge of that project, discussed this issue in a meeting
where Dr. Itakura, myself, Dr. Kleid, Goeddel, and I believe Giuseppe Miozzari were
present. We ended up deciding to rebuild the first five amino acids of the human growth
hormone by synthetic DNA and to facilitate the transcription of that gene by replacing
the human codons with codons which are easily recognized by E. coli. That experiment
was done by using synthetic oligonucleotides and eventually was a successful
experiment.
Hughes: Did you make those oligonucleotides?
Crea: It was still Itakura s lab. We, at Genentech, designed the oligonucleotides, but the
ultimate assignment to synthesize them went to Dr. Itakura and his laboratory. At that
time, we didn t have the lab ready.
Hughes: Let me clarify. At that point, your role in insulin was over; you d synthesized whatever
DNA was needed. As you well know, there were still people working on insulin,
interacting with Eli Lilly, et cetera. But you had dropped off that project?
Crea: Yes, the role of the synthetic DNA group was over after we confirmed that the genes for
A- and B-chains were successfully cloned and sequenced. From that point on, it was
37
more molecular biology territory, the expression in bacteria, and the final purification of
the two chains. If you recall, I was also involved in the purification of A-chain and B-
chain by HPLC. We succeeded in purifying and recombining the two proteins sometime
early in 1978. So from that point on, my role as a DNA chemist and a protein
biochemist, involved solely in the purification of the chains was over. I was really more
involved in managing this transition from City of Hope to Genentech. While other
people were trying to optimize the recombination of A and B, which was essentially a
protein biochemistry problem, I was already ahead on additional projects.
Hughes: That purification you did with the HPLC was an essential step, was it not? I understand
that one of the reasons or perhaps the reason that David Goeddel had been having
trouble was because the insulin segments he was working with were not very pure. Am
I on the right track?
Crea: Yes. There were two major challenges. One was to get all the oligonucleotides in a pure
form so that the assembly of the genes could go easily and smoothly, and then the
cloning and the expression could occur. The second set of challenges was purifying the
very minute amount of protein which was produced in the bacteria from the hundreds of
other proteins that E. coli produced so that we could get the A-chain and the B-chain to
reconstitute, to combine together, to form the native molecule, the human insulin. In
both cases, I was involved because the use of HPLC was under my direct responsibility.
Yes, perhaps the episode you are referring to was the gene, which the first time didn t
go together very well, and we had to repurify one of those oligonucleotides.
Hughes: When it is not purified sufficiently you get blockage by extraneous molecules that get in
the way physically?
Crea: Well, yes, you have a cross-reaction or contamination which makes it almost impossible
that two things find each other. It s like a male looking for a female in a haystack. You
have to look for the right counterpart. It s a different situation if you have purified and
clean molecules. They can find each other very easily. So, that was the case.
As I mentioned last time, the purification of A-chain went very easily, very well,
probably because it was produced in high amounts by the bacteria, and also because the
separation by HPLC between the A-chain and the E. coli proteins was relatively
straightforward. But with the B-chain it was a little bit trickier: not only because it was
in smaller concentration in the E.coli soup, but also it was more difficult to separate it
from the other proteins because of its chemical nature, and that is unpredictable. Until
you set up the conditions of your purification, you cannot anticipate how the
purification is going to be. If you are lucky you get a nice separation right away because
you have different entities that separate well under the conditions of the experiment. But
if you have, for instance, something that elutes very closely to the target molecule, then
you might have contamination. You might have to introduce another step for separating
two things that behave almost in the same fashion under the first set of conditions. In
experimental work, you start under a certain assumption, and then until you find out
from experience, you can t tell how easy or difficult it is going to be. In the end we did
purify the B-chain, and we collected enough material I m talking about a fraction of a
milligram so that we could run the recombination experiment in vitro, so that we
could finally demonstrate that we made a molecule which was exactly the same as
human insulin.
38
Hughes: And it really was? Because you told me last time that you weren t attempting to use all
the codons that nature uses. You ve told me that in terms of the growth hormones, you
were modifying what you needed.
Crea: Exactly. With insulin, nobody had isolated the human gene. That was one of the reasons
that we were so much under pressure at City of Hope and at Genentech to finish fast.
We were designing the gene from the amino acid sequence
Hughes: And working backward.
Crea: And working backward. We were looking at the human amino acid sequence, which
was known, and working backward to design a possible gene for the protein. But the
gene we designed was arbitrary in the sense that we picked codons for each amino acid
that were easily recognizable by E. coli as its own. So we tricked the bacteria to work
hard for us, giving them a blueprint of human insulin which was compatible with the t-
RNA repertoire of E. coli.
Hughes: Was there enough variation from the natural human insulin gene that you had doubts
whether what you had produced would function?
Crea: No, we were confident that the genetic code would apply to the work we had done. In
other words, you can pick among different codons, but the codons that we selected were
still coding for the human insulin s amino acids. The choice was really among different
codons which coded for the same amino acid, but that choice was dictated by what E.
coli liked rather than what the human cell liked.
Hughes: You knew what E. coli liked because of the somatostatin work?
Crea: No, we knew the preference in E. coli because of the database that had been generated
out of a virus that infects E. coli. In other words, there is a virus, lambda virus, that
reproduces itself well in E. coli. It can use the machinery of E. coli to reproduce itself
very fast. There was a sequence of the viral genes and there was a table which shows the
occurrence of the codons in the DNA of that little virus. So we took that as the basic
rules to optimize the transcription and translation of human insulin A and B in E. coli.
So we borrowed from a very small virus the secret of how E. coli protein synthesis
machinery works better.
Hughes: Had that data been published?
Crea: Yes, it was published.
Hughes: So you just turned to the literature.
Crea: Yes, we took the database out of the literature, and then one by one we looked at the
different possibilities, and we picked the ones which gave us the highest occurrence in
the codon choice of the virus. Today, the same criterion is being used for plant proteins
which need to be produced in bacteria and a lot of human genes that are cloned in
bacteria. So it s almost like redesigning the blueprint to fit the preferences of the
microorganism which is used. That worked out pretty well and was an effective piece of
work.
39
Hughes: What did you know or not know at City of Hope about Genentech s relationship with
Eli Lilly?
Crea: Well, one of the first corporate partnerships that Bob Swanson targeted once we started
the insulin project was Eli Lilly. It was clear to everybody in the company that Eli Lilly
was the largest manufacturer and marketer of bovine insulin, and they were recognized
as number one in the world for commercializing this drug for diabetics. So, it was the
obvious choice for the Genentech CEO and president to approach them and establish
negotiation with them. We knew that there was an interest at Eli Lilly to evaluate any
other alternative manufacturing technology to produce a human version of their drug.
We also knew from medical literature, from experts in diabetes and insulin that the
bovine insulin wasn t really an ideal drug for people with diabetes. The bovine insulin
after prolonged use caused some problem as related to immunogenic and antigenic
response, and that a number of patients were suffering from side effects. The side
effects ranged from typical inflammatory processes all the way to blindness and even
some cases of more debilitating diseases.
It was clear that there was a huge opportunity for Genentech to establish a partnership
with an industrial pharmaceutical company. The diabetic population was increasing
dramatically, bovine insulin was produced from animal glands, and it was a very
cumbersome manufacturing procedure, also subject to possible contaminations. Finally,
due to the rate of occurrence of diabetes, there would have been an increased demand of
insulin that the animal organs would not have met. So, there was a huge technological
opportunity for Genentech and there was a clear business target, which was Eli Lilly.
Swanson started negotiating with Eh Lilly, specifically with Irving Johnson, who was
Lilly s lead person, the champion, for exploring alternative manufacturing technology
for Eli Lilly. So, we saw people coming from Lilly to Genentech, or we heard of
meetings of Genentech management with Eli Lilly. As we were continuing working in
the laboratory, we knew that was an important milestone for the company. We also
knew that we were not completely off the hook in that after the announcement that we
had produced human insulin, I believe that Eli Lilly became more interested, but
ultimately they were asking some tough questions to complete the negotiations and cut
a deal.
Hughes: I ve heard it described that Eli Lilly wanted to see the insulin. Genentech could talk to
them forever about the new technology but Lilly wanted
Crea: "Show me the molecule." [laughs] For us, obviously, it wasn t a trivial exercise to
produce a milligram or even grams of the molecule. The major accomplishment at
Genentech had been the demonstration in the laboratory that this was a viable
technology, but we never did any scale-up production. But, it really was facing reality
for the company, in that the recombinant technology was just a component of the whole
story. Genentech would have to address additional important questions, such as
manufacturing, scaling up, purity, characterization, and down the road compliance with
the FDA and a body of regulations typical of the pharmaceutical industry before we
could claim that we had made a drug.
Hughes: But Genentech, at that stage, never contemplated doing that whole entire process, did it?
40
Crea: No, Genentech wasn t at the stage of claiming to the world that the company would
become a fully integrated company. We were still promoting the company as a unique,
technology-driven organization. It came later, after the success we had with human
growth hormone. That decision matured in Bob Swanson s mind. In retrospect, I
believe that the exposure and the experience and the relationship with Eli Lilly was very
instrumental to educate Swanson and the rest of the team how you become a fully
integrated pharmaceutical company.
m
Crea: If you took a snapshot of the company, you could see that the momentum was building,
because there was a lot of interest by the investors and that the management was making
the right decision, namely to bring in extra expertise for downstream process. If you
remember, one of the icons that characterized Genentech in the early days was a
fermentation apparatus which we built in the warehouse. Although it wasn t used very
often, because we didn t have much to do with it, it was a very nice icon. We took a lot
of pictures with the investors. That was essentially the challenge to Genentech: to
become a manufacturer of important protein-based drugs. Ultimately, the company was
capable of adding expertise in fermentation, in protein purification, in protein
characterization, and eventually all the way to scale up and purification under the GMP
[Good Manufacturing Practices] and so on. It was almost like a pipeline which grew,
having in mind this fully integrated organization which didn t want to depend upon
anybody else to discover and develop its own drugs.
Hughes: How much were you and the other scientists in the loop as to what Bob Swanson and
the other executives were doing?
Crea: Well, we were quite involved. I remember that we used to have staff meetings almost
every week. Those staff meetings would involve all the major players, from scientists to
attorneys to Bob Swanson, of course. We started discussing the business aspects in
addition to the scientific milestones. Also, because a lot of the early scientists were
becoming involved in negotiation of major deals. I remember the role that Dennis Kleid
had early on in negotiating a deal with Plum Island and the Army for developing a
vaccine for foot and mouth disease. I remember myself, being involved pitching to
Hoffmann-La Roche the human interferon project. I remember traveling together with
Swanson and Herb Boyer to New Jersey and having a meeting with the Roche
management to talk specifically about a corporate relationship for the development of
human alpha interferon.
Hughes: And they wanted you to come, because you could speak to the science?
Crea: Correct. Sometimes I would go and other times other people would go. So, the science
and the business became mutually supporting. We provided the technical contribution.
But as we met more and more managers from the pharmaceutical industry, we started
learning the language, we started learning the rules, we started learning the dynamics
that supported the relationship. That was a really unique school for many of us, and if
today a lot of scientists have become managers, especially out of Genentech, it is
because of that exercise that we went through over and over.
41
The scientific presence was extremely important for selling things, because everybody
was looking at Genentech as the pioneer, the best in this new industry called
biotechnology. They wanted to hear directly from the scientists about the novelty, the
uniqueness of the products and of the science. So we were very much involved. Not
everything of course was told to the scientists, and I remember sometimes there was
some uneasiness, if not a manifest complaint, with Bob Swanson of keeping us
scientists in the dark. The makeup of Genentech in the early days was mainly scientific,
with the exception of Swanson and some external expertise provided by Tom Perkins
and Tom Kiley. Ninety percent of the players were scientists. We were the majority, and
we had power in the organization. We were imposing on Bob to be more
communicative, to involve us more often in his business decisions. It was a very
dynamic, very interesting environment. We managed to elect a representative of the
scientific team to be present in each and every business discussion. Whether that
happened or not, I don t remember, but I remember that there were a number of
discussions with Bob addressing the specific need for the scientists and the key players
to be informed about business decisions.
Hughes: Did scientists appear before the executive board?
Crea: No, the board was more an abstract entity for the scientists. We knew about it, but we
never had a direct participation. Early on, the board was formed by only a few people
Herb Boyer, Bob Swanson, and Tom Perkins. We learned that as more and more
companies were investing in Genentech they would have a presence at the board level.
For instance, Lubrizol, which was one of the early investors in Genentech, asked for a
board seat. Don Murfin represented Lubrizol for many years. Later on, the board grew
to include experts in the field. This kind of event happened once more when Alpha
Laval made an investment in the company, and a representative of Alpha Laval, I guess
the president of the U.S. operation, became also a board member. But scientists were
not directly involved.
Hughes: Biogen had a really high-powered scientific board with several Nobel Prize winners.
But Genentech didn t go that way. Was it ever a discussion point, "Why don t we have
a scientific board?" The people on the Genentech board of directors were not scientists,
with the exception of Boyer.
Crea: I believe it was self-confidence, almost I would say arrogance being cocky. We
scientists were running the show. We were developing new technologies. We had an
unlimited power to come up with new things. Things were happening so fast that I
believe it was a mix of not recognizing anyone with the experience to drive that effort
and at the same time having Herb Boyer as the founding scientist, as the lead, the
scientific visionary as a representative at the board level.
Later on, Bob became sensitive to the need for the presence of key scientists as advisors
to the company. I think, in that respect, he relied on his connection with MIT to bring in
some heavy-duty, high-powered scientists to advise the company. So it wasn t formally
a board; it was more individuals who were hired to provide their expertise to the various
departments. In reality, we had access to very high-caliber scientists all over the United
States. Perhaps we were more informal, but the spirit of the team at Genentech was
informal too informal, in the sense that we were creating our own story every day.
42
We had this sense of power in the team that was sufficient to motivate everybody to do
the right things.
Hughes: I wonder too if there was an element of wanting to maintain control. If a company has a
high-powered scientific board, there could be difficulties. If you want to keep the reins
of power within the company, in the hands of Swanson, you don t want a Nobel Prize
winner on your board, saying, "Oh, no, that s not how to do things." Maybe I m
searching too hard. Maybe it was just the way the board evolved, the way it happened.
Crea: Well, it s never one or the other. Probably all of these things are true. It s a lot easier
for a young manager to have people who are not going to interfere with his job, and that
was true for us as scientists. We were not interested in listening to somebody else,
because there was too much excitement in what we were doing.
I remember the performance review I had with Bob Swanson for 1979 was very
positive. But his final remarks were as follows: "Roberto should seek the advice of
highly respected scientists in the field." To be honest, I wasn t interested in it because I
didn t want anybody to tell me what to do. I was one of the few chemists in the world
who would make DNA as fast as we did, and I didn t want any interference. I didn t
want to have to explain to somebody or to have the consensus of somebody. In
retrospect, I didn t react very well. It could have been different. I don t know whether
it would have made any difference. But I remember specifically that I didn t want
anybody to provide alternative ideas because I was perceiving that as a possible
interference of my work. I didn t want to talk to any gene machine expert. I didn t
want to talk to any DNA chemists, other than my colleagues. There was pressure by
Bob, because he had a chemistry background, to bring in some of his professors from
MIT. Ultimately, it was give and take: We hired a few consultants from Boston, MIT,
and we managed to establish a healthy relationship with individual scientists, rather
than forming a scientific advisory board as a body, who would coordinate rather than
dictate the scientific operations.
Hughes: Why did Bob suggesting that you should bring in outside expertise?
Crea: I think he was motivated by a number of reasons. The first one was the vision he had in
building the very best scientific team in the world. That philosophy was explicitly
manifested by Bob on several occasions. His philosophy was, "Let s hire the best." He
always insisted on hiring high-quality people. He made a bet on the very best in the
field, and he was right. So, he wanted us to do the same, not to compromise with low
quality, but to find and hire the very best in the field. The second motivation, I believe,
was the fact that we were building a business, and we needed to be recognized by the
outside world as the very best. Maybe Roberto Crea wasn t a name familiar to many
people and many investors. But if he had had Professor So-and-so from Harvard or
MIT, it would have made the overall vision of the technology and the technical team
more credible. That is a strategy. That makes sense. I m not saying that it was
motivated by a window-dressing philosophy, but he knew that bringing in the most
recognized names would benefit the company from more than one angle.
Hughes: Do you remember ever having a discussion with him on this point?
43
Crea: Yes, I remember my resistance and my skepticism about involving other chemists with
big names because I was afraid they would shed me.
Hughes: But you were very young, despite your accomplishments.
Crea: I was very young. I was still in the mode of establishing myself. More than anything
else, I was afraid that a more established name in the industry would take advantage of
what we had done to get the credit. I had seen that before, including past experience
where you do most of the work, and somebody who can speak well and present well
gets the credit.
Hughes: Did you have a relationship with Swanson in which you could say this kind of thing?
Could you talk to him in this manner?
Crea: Yes, I had a nice relationship with Bob. I mentioned that we shared the apartment
downtown for more than a year, so we were not only involved in the same company as
boss and scientist, but we were sharing some relaxed moments in the evening. I was
playing in the kitchen. I was experimenting my Italian cooking ability with Bob, and
we had many occasions when we could talk freely and share our thoughts with each
other. Although during the working hours, Bob was very professional. Outside that he
would really come down and be almost playful and boyish with the rest of the team. He
was a wonderful person who could put himself at different levels and open up with his
colleagues. So, specifically the answer is yes, I told Bob. But Bob was persistent. As I
said, I was listening to him as a big brother. I tried not to go one hundred percent his
way, but to go his way ultimately.
Hughes: In these first years, the scientists became concerned that some of the new people being
brought in did not meet the highest standards. Does this ring a bell?
Crea: It was easy in the very beginning when the Genentech team was still thirty, forty, fifty
people to share opinion and decide by consensus. So the hiring we were doing was very
good, high quality, because we were all participating. When the company started
growing, adding lots of people every week, it became more difficult to monitor that
selection or to participate in that selection. So you can imagine that in a fast-growing
organization, your colleagues are not interested as much in participating or interfering
with your business, and therefore you can enjoy more freedom in your selection. On the
other hand, there is more risk because you might hire somebody who ultimately rums
out to be mediocre and find out later that you overlooked or underestimated a defect.
So, in a way it is a positive and negative having total control of the decision in bringing
in new people, because one person s judgement is not as good as that of many people.
It s possible that later on, some of the people hired at Genentech didn t turn out to be as
good as we thought.
Hughes: It may have happened after you left, but somebody talked to me about a hiring
committee because this problem of mediocrity had gotten to a level where people
thought something had to be done that it wasn t acceptable to have a division head on
his own hiring a new scientist without some common set of criteria. I thought that it
was formalized as a committee, but I may be wrong; it may have been more informal.
44
Crea: No, I don t remember. Maybe it happened after I left. My experience in the company
was a mixture of success and failure. I hired early on a chemist who turned out to be an
arrogant person who gave us a lot of headaches. At the same time, we hired another
person from Yale University who turned out to be a wonderful scientist and a wonderful
person. It s really difficult, hiring and selecting people, even if you have a committee.
But it s true having more than one person, especially people who are trained to see
through the fa9ade and the good things that you hear from candidates, ultimately
minimizes the risk of hiring mediocre people.
Hughes: I should have asked this earlier. Did you go to the press conference announcing human
insulin in September, 1978?
Crea: Yes.
Hughes: Can you describe the situation?
Crea: I remember that that was a big event, but it wasn t my first press conference, because, as
I mentioned before, I participated in the first announcement by Genentech of the
successful experiment with somatostatin. The City of Hope press conference was
obviously more important. It was a clear disclosure to the world that this technology
that we mastered was going to become an important component for the pharmaceutical
industry, and perhaps for many other industries, like the food, the environment, the
energy. It was a major show which was planned carefully by both Genentech and City
of Hope.
Hughes: Was one of the points of the press conference to show the attendees that this technology
could do far more than produce just insulin?
Crea: Swanson had that message in his presentation. But I believe that at that conference,
more than the broad applicability to the industry, the focus of the presentation was on
health care, the benefit to humanity from a medical standpoint. The strong message
was, "Now we can make for the first time a human protein which will benefit millions
of people. If today we can make insulin for diabetes, tomorrow we ll be able to make
other drugs for people with devastating diseases, like cancer or cardiovascular." So the
emphasis was the power of technology for medicine, for saving lives, or for providing a
slew of new drugs.
Hughes: Were those goals a motivator for Roberto Crea?
Crea: For me it was like Disneyland. It was a wonderful set of events. I was flying high. I
was in the picture, contrary to what had happened for somatostatin where the focus had
only been on Dr. Itakura and Art Riggs. The insulin breakthrough officially identified
Dr. Roberto Crea as one of the protagonists of new technology the biotechnology.
m
Crea: From that point on I was treated as one of the major players, and I believe I deserved
that. It was fascinating how the laboratory events had unfolded in a worldwide front
page media event, and I was enjoying every minute of it.
45
The City of Hope press conference had two tables, one on the left side of the podium
with the City of Hope scientists. I remember it was me, Dr. Itakura, Dr. Riggs, and
Tadaaki Hirose. On the other side of the podium was the table with Robert Swanson,
David Goeddel, and Dennis Kleid. The chairman of the meeting was Dr. Rachmiel
Levine from City of Hope. The conference started with an introduction by Dr. Levine,
followed by a presentation by Bob Swanson. The flash of the photographers bulbs, and
the noise of the cameras, and the heat of the day, and the crowd were all a fantastic and
surreal experience. I didn t get a chance to get up and talk about my work because in
the midst of the presentation we had a power failure. Not that I was one of the main
speakers, but I was ready to answer questions if somebody in the press would have
asked about the synthesis of the genes. But as Dennis Kleid took the microphone and
started talking about the importance of the discovery, we had a power failure. That
could not be fixed, so the media started to leave the room, and we took some journalists
for a tour of the laboratory.
Hughes: It was a new experience for you.
Crea: Well, I had just accomplished thirty years old in July, so for me it was an incredible
adventure. It was so exciting to make history and to see my name published in the
newspaper or in scientific magazines. It never happened to me before and it never
happened again in that form.
Hughes: Is there a story about the published papers? There are two of them: one by the cloning
group and one by the DNA synthesis group.
Crea: Correct. There was pressure on the group collectively to publish the data before we had
a press conference. Otherwise it wouldhave been perceived as bypassing scientific
integrity, and in that respect, we didn t want to disclose anything to the press prior to a
scientific paper being accepted by one of the most prestigious journals. The two papers
were prepared to describe the two aspects of the insulin story, namely the chemical
synthesis, and the cloning and the expression. Obviously, in terms of news and
scientific importance, the production of insulin was bigger news. So the focus was on
getting first the expression work ready for publication and later on coming up with the
synthesis of a human insulin gene. We managed to get on a fast track, because the
policy of the journal that we targeted, the Proceedings of the National Academy of
Sciences, is that if the paper is reviewed and submitted by a member of the Academy it
is automatically accepted. So we managed to get the review of Professor Ernest Beutler
in Chicago.
Hughes: Somebody on the team must have known him right?
Crea: Professor Beutler was a member of the academy for his contribution in biology, I think,
but he was also a professor at the City of Hope.
Hughes: Probably Riggs set it up?
Crea: Riggs must have set it up.
46
Actually, I have to correct myself: the chemistry paper came first. The chemistry was
published in December, 1978, and the expression paper came a month later. But they
were submitted side by side October 2 and October 3,1978.
Hughes: Is there a story there? One could argue that it made sense to publish them back to back
in the same journal issue.
Crea: It must have been some detail in the paper, some comments by a reviewer, that
postponed publication of the expression paper. Yes, it would have made sense to have
them side by side. Actually, if I remember well, it s not that. It s a policy of the
Proceedings to publish not more than one paper every issue by the same author. So, we
couldn t publish side by side in the Proceedings. So, we compromised with the
publication of the chemical synthesis and immediately after came the expression paper.
Hughes: Who are the authors?
Crea: In the chemical synthesis, obviously I didn t have to insist that I would be the first
author. In any event, it was okay, because Dr. Itakura was the senior author, and he was
the last, but I was the first. This is still if not the most important publication that I ve
done, one of the most important publications. The other paper had Goeddel as the first
author and Dr. Riggs as senior. So, we were happy. I worked on the chemistry paper
together with Dr. Itakura, and of course our strange English was probably edited by the
rest of the Genentech team. But we got the paper in good shape to provide the most
important experimental design and details. It got accepted and published two months
after we submitted it.
Hughes: That was very quick.
Crea: It was very quick, but the nature of the work was unique.
Hughes: It was evident in the expression paper that Goeddel should go first and Riggs should go
last, but the order s not evident for the people in between, of which there are many.
Was there any discussion?
Crea: Yes, of course. There was a discussion among the authors. I believe that the criteria
which were used identified the Genentech team, the San Francisco team, as the most
important authors of this paper, and City of Hope as second important. So, the names in
the insulin expression paper refer to the San Francisco team, namely the Genentech
team and the UCSF team. Later on, the order of the authorship reflects the contribution
of the chemists, mine and the others, and finally Art Riggs as a senior author as one of
the key people in preparing the experiments.
Hughes: The conceptual basis?
Crea: Yes, in the conception of the expression. Interestingly enough, Dr. Boyer is not part of
this paper.
Hughes: Exactly. [Pause.] Are you going to explain? [laughter]
47
Crea: I believe that it must have been a very tough decision. I can t be sure that I understand
all of the reasoning behind the decision. On one side, I can say that technically
speaking, the work had been accomplished by the authors, and that Herb Boyer was
never involved from the experimental standpoint. But obviously the argument that he
was one of the minds behind the project would justify the presence of Professor Boyer
as an author. So, I believe that it was a mix of scientific rigor as well as perhaps some
corporate reasoning to specifically identify the work as generated by Genentech and not
by UCSF.
Hughes: That s interesting, because one of the things that I have heard, and I must admit not
specifically tied to this paper, is that Boyer from the start of Genentech wanted to step
back and give the young scientists a chance. How true was that really? Is that handy to
project now?
Crea: No doubt that Herb was the mind behind Genentech science, and if it wasn t for his
contribution at the level of recombinant DNA and his involvement with Swanson, there
would be no Genentech today. But it was a mix of respect for the young scientists who
were making things happen, and I would say also the sense of maintaining a position
which could not be identified too much or too often with the industry. Herb was under
tremendous pressure as a professor at UCSF not to step too much into the business side
of science. He may have decided it was a good thing to do to let the young bright
scientists get the credit for taking the technology to the next stage and not to expect to
center all the scientific attention upon himself. I think that we appreciated very much at
Genentech his integrity. In retrospect, Boyer could have had more visibility as a player
at Genentech, but I think that he didn t need it, on one side. He was very sensitive not
to be perceived as a person who wanted to take advantage of things in which he hasn t
participated, at least from an experimental pointof view.
Hughes: As you are probably thinking, in 1977 and 1978, he was being criticized for having
commercial ties while remaining a professor at the University of California at San
Francisco. So, maybe it would have only intensified that criticism if he had appeared as
an author of a paper on research which in large part had taken place at a company.
Crea: Yes, I believe that there was a lot of criticism and not only in the corridors of UCSF.
The press started publishing articles which weren t positive for this hybrid position of a
scientist and entrepreneur. That debate went on for several months, maybe years, and it
was almost becoming paranoia to get associated with a small business if you had a
prestigious position in academia. We were also aware and shared that frustration and
that pressure with Herb, because that ambiguity which had been created by colleagues
and press continued hunting Herb for many years. We all felt that he deserved to have a
Nobel Prize for his discovery and that ultimately his association with Genentech had
compromised getting that big reward. Whether that corresponds to reality is always
going to be difficult to know. But it was in our mind every day that Boyer was almost
singled out by the academic community as this rebel who stepped over the code of
scientific integrity and was trying to make himself rich and famous by an association
with an industrial enterprise.
Hughes: So there was quite a bit of talk about that at Genentech?
48
Crea: Yes, we were just sharing his unhappiness and uneasiness, because he never wanted to
relinquish his position with UCSF. But he found himself in the eye of the cyclone of
biotechnology and the growth of a tremendous industry, which eventually became one
of the most exciting revolutions of the past century. Whether he wanted to do that, it
wasn t upon himself. It was out of his hands. So, he tried to do the best out of it.
Hughes: Interesting circumstances.
Crea: I can add something else. We as the scientists were very much concerned that the
quality of the science at Genentech would be as high or higher than any academic
laboratory, because we didn t want to be perceived as mercenaries or second-tier
scientists. So in that respect there was tremendous sensitivity and awareness for the
quality of what we were going to publish. Fortunately, we had a leader in Bob Swanson
with a vision of not compromising quality of the science. So all the publications that
came out of Genentech now are considered one of the most beautiful examples of
scientific experiments and scientific discoveries.
The discussion of science and the application of science was very much alive among the
young scientists who had joined the company early on and the scientists who had joined
the company later on because of the impression that commitment to leave academia to
join a biotech company was the equivalent of choosing money versus glory. Ultimately
that was proven to be wrong.
Hughes: Shall we move to the patent?
Crea: Sure.
Hughes: The Riggs-Itakura patent didn t issue until 1987, but was applied for in 1978.
Crea: Before that. Maybe 76.
Hughes: Were you involved in that discussion?
Crea: No, I wasn t.
Hughes: Why were certain people included and others not?
Crea: Well, in my mind and in everybody s else mind, I believe the conception of producing
proteins from recombinant DNA technology was born in Boyer s mind and in
Swanson s mind, back as far as 1975 or 76 when they first met. The execution of that
strategy essentially took place at City of Hope. The most relevant experiments unfolded
as the synthesis of the gene was perfected, as the cloning was perfected, and as we
found the expedient to produce a stable protein in E. coli. City of Hope was essentially
relying upon two laboratories: one was headed by Art Riggs and the other one was
headed by Keiichi Itakura. In retrospect, the invention of expressing heterologous
proteins in E. coli happened in those two laboratories. The patents, which capture the
novelty of those inventions, were written to reflect the execution of that plan and bear
the names of the heads of the laboratories.
49
It s a very debatable field. One can make the argument for giving the paternity of those
patents to Art Riggs and Dr. Itakura, and somebody can make an equally valid argument
to assign the authorship, the inventorship, of those two patents to Boyer and Swanson.
The patent law is a very complex discipline and by no means do I want to represent that
I m an expert. But I believe that everybody can understand the conception of an idea
and the execution of an idea, so that s where the key issue lies. Should a patent
recognize the person who has conceived the idea or should a patent recognize the
person who executed the idea, and embellished the idea, and eventually demonstrated
the idea? The patent law says that you need two things: to enable somebody who is
skilled in the art to reproduce your invention. In that respect, if you don t have any
laboratory work, you don t have any invention. I don t believe that the possibility of
producing proteins from bacteria, which was conceived by Boyer and Swanson at
least we can assign a portion of that paternity to them I don t think that that by itself
would have been sufficient to qualify for inventorship on a patent. That the only
authors should be Professor Riggs and Dr. Itakura can also be perceived as limiting.
But these are decisions that are typically discussed among the participants, the players,
the attorneys, and ultimately it is what it is. The patents were filed by City of Hope and
assigned to Genentech. Sometimes it s a matter of strategy.
##
Crea: I can think of a second scenario where the patent could have been filed by UCSF. But
UCSF was not involved in the experiments, so they didn t have any title
Hughes: Well, it was involved in somatostatin.
Crea: They could have filed a prophetic patent. Prophetic means when you conceive an idea
that in your mind can be accomplished because all the components that are required for
the experimental work are known. But in this case they were not known. We didn t
know what to expect from bacteria until we did the experiment. So really the
alternatives weren t many. Actually, I should say that there were no alternatives,
because the third scenario could have been that Genentech filed for patents. But
Genentech at that time didn t have any laboratory or any scientific personnel. So in the
end, it was a good compromise from a business standpoint to let City of Hope file under
the contract relationship and the understanding that those were patents exclusively
licensed to Genentech.
Hughes: Herb Heyneker springs to mind. As you know, he was a postdoc, being paid by
Genentech, in Boyer s laboratory at the early stages of the somatostatin work. Then he
dipped in briefly in the insulin work when he came back from Holland. It must have
been before you arrived when there was a problem with a flipped codon. He and David
Goeddel went down to City of Hope and worked furiously to figure out what was
wrong probably not enough to make a patent claim. In the first instance, Heyneker
was a UCSF postdoc, paid by Genentech. In the second case, he was only a prospective
employee of Genentech. So it is not a really strong case, is it?
Crea: No, it was a complicated situation. In the end, in my opinion, it was a good compromise
because there was a clear distinction between the work that was supported by
Genentech at City of Hope and the contribution of other scientists at UCSF. It would
have been a lot more difficult to share that patent with UCSF and cut a deal with UCSF,
50
even if you could relate some of the invention to UCSF employees. It was a clear cut.
It was reality. It was a good compromise between recognition that maybe not
everybody was entitled to participate in that invention and the fact that ultimately
Genentech was getting the exclusive rights to exploit that patent.
Hughes: By being the exclusive licensee?
Crea: Exactly.
Hughes: Was that part of the deal?
Crea: That was part of the deal. It was clear that there would not have been any commercial
application of recombinant DNA technology without Genentech supporting the effort at
City of Hope. So it was clear that any commercial implication of the research that we
were doing at City of Hope would have been exploited by Genentech as a company.
Hughes: I meant, was it understood from the start of the patenting process that if a patent issued
Genentech would be the exclusive licensee?
Crea: I think that was part of the initial contract. I cannot imagine, although I have not seen
the contract itself, but I cannot imagine out of my twenty-plus years experience in the
industry that the company wouldn t expect full rights to a program which is sponsored
financially by the company itself.
Hughes: There s a precedent for that, isn t there?
Crea: Oh yes, it s almost the ABC of business, especially when the technological risk
involved in the research work is being supported by a company. There was no
assurance for Genentech that this would ever work. This situation was contrary to a
case when a company goes to an institution Stanford, MIT, Harvard and licenses a
patent. In this case the research is already done, and the company has the benefit to
evaluate the potential, prior to committing any financial means. In the case of
Genentech, it was pure speculation that this technology would work. So what would
have been the reward for taking the risk other than exploiting commercially the
inventions of those patents? Anything to the contrary would be uncivilized.
Hughes: Well, perhaps we could stop with any observations you have about intellectual property
policies in those very early days at Genentech.
Crea: It became clear with the Genentech phenomenon that intellectual property was one of
the pillars upon which the industry was going to be built. That science perfused from
academia into the industry and later on from the industry into the academia is an
argument that can be made. It was a cross-fertilization between laboratories at
Genentech and laboratories in academia. And it s always the case because science
speaks the same language whether it s done by a commercial enterprise or by
researchers in academia. But the only way companies can survive is if they have a clear
protection from an intellectual property standpoint. So, conceiving a commercial
enterprise without strong intellectual property is almost building on sand. So, as the
biotechnology industry in its infancy started growing, it became very, very clear that the
only way to survive and flourish was to access a strong IP. If you could do it in your
51
laboratory, it was fine because it was one of the major assets that the company could
build. But if you could access intellectual property from academia through licensing, it
was also a valuable alternative. So, many companies in the early eighties took the
approach of licensing technology from the most prestigious institutions, like Harvard,
MIT, Stanford, and Berkeley. That is not different from what happened in other
industries, like the electronics industry. But for biotech it was extremely important,
almost essential, to rely on intellectual property to build a business upon something
unique that nobody else could access. So the patent world got an incredible boost from
this new biotechnology. Hundreds of patent attorneys start getting involved in this new
field as it became clear that it was an exploratory, fertile ground for inventions for years
ahead. Genentech was very smart and very fortunate to have somebody like Tom Kiley
early on to take care of that aspect. I think that the work that Tom has been done in
identifying intellectual property and protecting intellectual property at Genentech is
almost textbook.
Hughes: There were some uncertainties in the early days about patents in biotechnology as a
field. Do you remember that patent applications were held up for a while, waiting for
the Chakrabarty decision? At the time, there was a fair amount of talk in the press about
even if the patenting of life forms is allowed, will these patents stand up? Do you
remember any discussion like that?
Crea: I remember very well, because that was a major, major decision for the biotech industry
at its early stage. I believe that if the Chakrabarty patent had been denied, it would have
killed the industry right there, because most of the work that was being done by biotech
companies was centered around living organisms and life and biological events. So that
event was saluted with a great deal of enthusiasm by the entire industry. That shows
you the visionary, illuminated gift that this country has in supporting innovation and
creativity. It s amazing to think of the disastrous effect that it would have had if the
Supreme Court decision had gone the other way the denial of the majority of the
biotech patents. So thank God things went the way they went.
Hughes: Was the Supreme Court decision a subject of discussion among the scientists at
Genentech?
Crea: Oh yes, although there was a feeling that we couldn t do much about it. We were
talking about it. I think that Mr. Kiley played an important role during that period with
his testimony before Congress in favor of patenting biological forms. 1 So, if science
wasn t directly involved, the representative of intellectual property at Genentech was
heavily involved in that debate.
Hughes: Should we stop there for today?
##
1. Kiley wrote an amicus curiae brief for the Chakrabarty Supreme Court case of 1980 (Diamond
vs. Chakrabarty, 447 U.S.303 [1980]).
52
[Interview 4: August 29, 2002] ##
Hughes: Dr. Crea, give me your observations of the atmosphere at Genentech in those very early
days.
Crea: We re going back to the beginning of 1979. As I mentioned to you, I got to San Francisco
in the summer of 1978, and I was mainly setting up the lab, putting equipment together,
hiring some people. The early days at Genentech were characterized by a flurry of
activities in that we were trying to move some projects ahead. At the same time, we were
recruiting good people from all over the country and maintaining a healthy dialogue with
City of Hope. At the same time, we were focusing on some important collaborations with
outside scientists, especially scientists who were working on the human growth hormone,
insulin, and interferon projects. Specifically, what comes to my mind is a collaboration
with Peter Seeburg from UCSF, Axel Ullrich, also from UCSF, and other scientists,
mainly from academia. But also we were exploring collaborations with companies, like
Eli Lilly and Hoffmann-La Roche. We were also focusing on our own projects, projects
which we could initiate internally and carry forward without any additional help or
participation by other scientists. It was very intense because the scientists were gathering
together quite often in the presence of Bob Swanson, or even without him mainly to
discuss the progress of the scientific experiments, but also to look ahead to the new
proteins or old proteins that could eventually be produced by recombinant DNA.
Hughes: Was there a lot of interaction? For example, the cloning group might make suggestions to
the DNA synthesis group, or vice versa?
Crea: Not really, not with respect to DNA chemistry. DNA chemistry was up and running from
the beginning. In essence, the technology had been transferred from the City of Hope. We
took with us quite a bit of material, we shared a library of dimers and trimers, but
essentially the methodology was well established. We had equipped the laboratory with
all the necessary instrumentation to do both the synthesis and purification of DNA. So
really there wasn t much discussion around the priorities of my department because since
the very beginning my department was perceived as quite productive. So, if people were
asking for DNA, they were getting it. It was more a matter of priority: which one comes
first? Which one comes later? The basic approach or methodology was never discussed.
Hughes: I didn t mean that so much. But there must have been some coordination that had to be
arranged, and you just mentioned that: who needs what primer first? And when might
things come from City of Hope? That was still happening, was it not?
Crea: We decided early on that City of Hope would participate in the human growth hormone
project. That was dictated by some contingency the lab wasn t ready at Genentech, so
we had to get things going while we were setting up the laboratory, hiring the first
scientists. That project was discussed early on with Peter Seeburg, Goeddel, Kleid,
Itakura, and myself. Miozzari was also part of that discussion. That decision was
essentially unanimous to maintain a relationship with City of Hope and to get the
fragments which were necessary to complete the gene from Dr. Itakura s laboratory.
Hughes: You didn t have any adverse feelings about that arrangement?
53
Crea: No, none whatsoever. I think at that time, I was not too much interested in the business
relationship between Genentech and City of Hope. For me, it was something that
Swanson had taken care of, and it wasn t our job to dig into the business relationship. Our
job was more to get the project moving and done quickly. There was this sense among the
scientists that we were in a very competitive arena and in a race to express and produce
novel proteins.
Already, with human insulin, there had been a lot of pressure to expedite the synthesis
and the expression because we knew that there were other laboratories which were
working very aggressively. The word was getting out very quickly that we had a very
powerful machinery at Genentech to do more and more, better and better, and address the
next challenge. Our assumption was correct in that other laboratories, once they figured
out how to do it, once they saw the publications, and they looked at the work Genentech
had done with human insulin, were going to reproduce or try to do the things that we were
doing. We were trying to put distance between ourselves and the rest of the world by
really moving quickly into more ambitious projects.
Hughes: Seeburg of course eventually came to Genentech, but when you first arrived at
Genentech, he was still at UCSF. Did you think of him as a collaborator while he was still
at UCSF, or was he somewhat of a competitor?
Crea: He was perceived as one of the top leaders in the area of human growth hormone. We
knew that he was working in Howard Goodman s laboratory at UCSF. But somehow,
from my point of view, we saw Seeburg coming to Genentech early on it must have
been the fall of 1978 with the clear intention of working with us, almost a recognition
that he couldn t do it by himself. I knew that we couldn t do it without him. So there was
a genuine sense of synergy and complementarity when we first got together in that he was
bringing years of experience in the specific cloning of human growth hormone and
bovine growth hormone. We were adding two major components to his work, namely the
ability to fix the gene which was not complete when he sequenced the gene, and to clone
and express the gene in a much more efficient way than he could do it by himself.
Hughes: When you say fix the gene, you are referring to the fact that it was part synthetic?
Crea: Correct, I am referring to the fact that I was told that the gene wasn t complete. The
sequence that had been isolated at UCSF was missing a portion, and we had to
reconstitute that portion with synthetic DNA. That was exactly what we told Dr. Itakura
to do early on: to synthesize the necessary oligonucleotides to build up the portion of the
gene which was necessary for the coding region of the first twenty three amino acids.
Hughes: I believe that the San Francisco group was using a complementary approach. Why was
the gene incomplete?
Crea: You are correct. The technology at that time wasn t effective and efficient to isolate
genes. So the approach they were taking at UCSF and many other laboratories was to
start from probes from pieces of the gene and then try to copy the remaining gene. Very
often you can pull out only partial sequences, so it is not a given that you can isolate the
whole gene.
54
Hughes: So, Seeburg was as interested in joining you as you were in having him give you some of
the technology that he had developed? It was very much a synergism?
Crea: I believe so, because, again, we had showed the world that we could move very quickly
with the synthetic DNA and with the gene expression. We had all the tools to do it by
chemical synthesis. At that time, the chemical synthesis of human growth hormone would
have been a very challenging business because the protein is a very long one; it is one
hundred and eighty-one amino acids, I believe. The insulin gene (A and B) all together
coded for fifty-one amino acids. So there was a three- to four-fold difference. It would
have been at least a year, a year-and-a-half work in the chemistry department alone. We
felt that there was no need to wait that long if we could patch the natural gene together
with the synthetic DNA and complete the sequence of the gene and of course, the other
elements necessary for the expression of the gene in E.coli.
Hughes: How confident were you that a patched gene would actually have biological function?
Crea: Well, the insulin experiment was a very compelling one. The gene that was used for the
production of human protein in bacteria wasn t a human gene; it was a man-made gene
that we designed ex novo from information that we found in the literature on usage of
codons in viruses and E. coli. So it was clear that we could trick the bacteria by giving
them a blueprint which is easily readable by the bacteria because bacteria don t really
mind what they are going to assemble. It is almost a mechanical assembly. Once you have
created the right blueprint, you can produce almost anything, unless the protein produced
is toxic to the bacteria. But at that time, we didn t believe that human growth hormone or
any other human protein could be intrinsically toxic to bacteria. It was a good guess to
embark on this project with the idea that what was missing from the isolation of a gene
from human tissues could eventually be replaced by synthetic DNA.
Now I am trying to recollect exactly this set of events. I believe that soon after we
completed the gene, we tried to express for the first time human growth hormone. We
noticed that the production of the protein was not very good. We couldn t explain why we
couldn t see much of the protein from bacteria on gel chromatography. We got together
to discuss which problem could account for the poor expression yields of the human
growth hormone. There was a suggestion I don t remember now who made that
suggestion to refashion the front part of the gene to be more readable by the bacteria. In
particular, one of the codons used was a very rare codon which is seldom used by E. coli.
It was almost like a break in the translation of the DNA. That was an excellent guess,
because as we changed that codon into a codon preferred by the bacteria, the yields went
up tremendously, by orders of magnitude. So, it was clear at that time that there were
some specific requirements to get the best out of the E. coli machinery in terms of
manufacturing proteins.
Hughes: How intensely were you and others working by 79? You had been there roughly a year.
Crea: In the early months at Genentech we had probably a dozen people, not more that two
dozen. So, it was a very small group. It was almost a second family for all of us, and we
were all young and energetic. It was more a personal challenge to give the best to make
this company succeed.
55
Hughes: Was there also a little competition amongst the scientists? The cloners didn t want to fall
behind the chemical synthesis people?
Crea: I wouldn t say that it was a competition. It was more a mutual pressure; we were putting
pressure on each other. Then on top of it, Bob Swanson was putting pressure on all of us.
Among the scientists, there was no competition because there was an awareness of
complementarity of skills. I wasn t trying to get into molecular biology and vice versa;
nobody was trying to do the chemistry. It really was a team effort. It was almost playing
together, a major challenge where everybody was asked to produce at his best. In that
respect, there was no clock. We were working essentially from morning to evening to try
to get to the endpoint of specific assignments as quickly as possible. The rest was good
execution, good people around, good teaching, good practices of methodology. Every
time you start something in a brand-new laboratory, you need to almost debug the system.
Things don t always work as you want. Every time there was a new goal, a new project, it
was an opportunity for us to try to do better, faster, and more efficiently. That was, for
sure, the work in the chemistry laboratory.
The chemistry that we developed at City of Hope, and then at the early stage at
Genentech, was called solution chemistry. In other words, we were doing the assembly of
blocks in solution. As we started working at Genentech, one of my goals was to expedite
the synthesis. I came up with the idea of doing it by solid-phase synthesis where you
attach the first base to the solid support. Then you build the chain on a solid support, and
that would give you some advantages in terms of purification and additional synthetic
steps. The solid phase was the next goal for the chemistry department with the intention
of putting together technology that could be eventually automated by machine, by
instrumentation. So we never did routine work. Every time it was trying something
different and new to do better and faster.
Hughes: Where had you gotten the idea for fixing the molecules? Solid-state means, you
immobilize them on some kind of surface? Was that a principle of chemistry that you had
adapted?
Crea: Well, actually, it was the training I did in Holland. In Holland, I started a project for the
European Community to immobilize molecules on a solid support. I was very successful
using cellulose out of the box and attaching complicated molecules to cellulose. One of
the first works that I published as Genentech director of DNA chemistry was indeed a
chemical synthesis of DNA on cellulose. Cellulose was a particularly easy-to-handle
material. The paper I m referring to I published with Thomas Horn in Nucleic Acids
Research? and that paper was also presented at an international symposium in Hamburg
in 1979. That paper had the title of "Synthesis of Oligonucleotides on Solid Support
Cellulose."
I was looking at the experience that I had before I joined City of Hope and Genentech,
and tried to combine the good things that I learned early on with the new challenges. At
Genentech, we used cellulose for a number of years in making synthetic DNA. I believe
that there was a patent application. Ultimately we realized that there were other polymers
that could function as a cellulose. But at that time it was a novelty because we could grow
l.See Crea bibliography, 318, in the appendix of this volume.
56
a synthetic chain on a solid support very easily and then release the oligonucleotides from
it and obtain DNA for gene assembly or other experiments.
Hughes: Were the other DNA synthesis labs, such as Narang s or Khorana s, adopting and
adapting this solid-state approach?
Crea: Yes, but, in particular there were no successes around the world, because in effect the big
push in the chemistry of DNA happened during those years, when everybody started
realizing that DNA synthesis is as powerful as any other molecular biology tool, if you
want to build genes. So, the big rush in DNA chemistry occurred after we published the
synthetic DNA for human insulin. I remember laboratories in Colorado and other
laboratories in the United States were doing some basic work. But the big pressure of
taking that basic chemistry, that basic knowledge, into applications, namely, turning that
basic chemistry into molecules that you can use in bacteria to produce protein, really
occurred after human insulin was expressed in bacteria via a synthetic gene. So, what we
saw in 1979 and then later on, was a flurry of activities in laboratories to improve,
expedite, modify, and develop new tools, including the gene machine.
From my lab s point of view it was, let s not defocus from the job that we have here at
Genentech. Let s not try to chase everything that might be perceived as an improvement,
because our chemistry works and can support the current effort, which now is becoming
more centered around the molecular biology. I didn t want to change too much. It was
more like, let s produce, let s get there first, and then maybe we ll have the time and the
financial latitude to play fancy chemistry.
Hughes: That is interesting, because someone mentioned to me that Cetus in his opinion wasted
time in developing the technology. In this case I guess he was referring to recombinant
DNA technology. The approach he described for Genentech was that they went after
products. I suppose that implies that if Genentech needed to improve the technology, then
it would, but only in the context of getting the product out.
##
Crea: Genentech was more pragmatic go get it; be there first; we have to beat everybody else.
This message was constantly repeated by Bob, who was coming into the laboratories
often, talking to the scientists to monitor progress. He wanted to get there first. It was a
very sound strategy, a very understandable philosophy. We were small, undercapitalized,
and relatively unknown to the world. We had to perform better than anybody else to gain
legitimacy in the new industry. Once we did, we wanted to maintain that leadership.
In 1979, 1980, it was more, "We are the only one or the best one in the business; what we
can do is almost unlimited. Let s go and be smart in selecting the targets and try to beat
everybody else." Nobody had the set of skills and set of tools that Genentech had
assembled in the first year or two.
Hughes: Did Cetus ever feel like a formidable competitor? They were already up and running in
1971. So they had a bit of a lead.
Crea: Cetus was always perceived as one of our competitors, if nothing else for their close
proximity. If nothing else, we could feel the pressure from the other side of the bay, and
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the sense was that Cetus had the financial latitude to beat us. They were a lot better
capitalized; they had more money, more scientists. We didn t have that luxury. We only
had the luxury to compete from a skill set and our ambition to be the best with less
financial means and perhaps fewer human resources than Cetus. Bob used Cetus and Dr.
Peter Farley, the president of Cetus, as the threat coming from the other side of the bay to
motivate the scientists at Genentech. The other major competitor, although distant, was
the group of Wally Gilbert, Biogen, and their European connection with the University of
Heidelberg in Germany and Basel in Switzerland.
Hughes: What was the connection with Heidelberg University?
Crea: There was a group of well-known scientists in Germany who were joining Wally Gilbert.
Hughes: Oh, that was the Biogen connection?
Crea: Yes, there were scientists from Germany, from Belgium, and from Switzerland, joining
the Biogen effort. It was definitely a very skilled group of people. It was always a fact
that they could come up with the next breakthrough before we did.
Hughes: Were you as a group monitoring the literature?
Crea: All the time. Not only the literature, but we were very sensitive and intent to what was
disclosed at symposiums and international meetings. It was having our antennae up
almost all of the time to gather information. A fascinating thing occurred when we were
trying to gather intelligence from competitor groups. It became apparent at the
symposium on interferon, which I believed occurred in 1980. Everybody was in a race of
isolating interferon and getting a partial sequence, because a partial amino acid sequence
would have given out the clue how to go back and synthesize DNA probes and attempt
the isolation of the whole gene. Genentech didn t have any information yet on interferon.
Genentech didn t have any leadership in the interferon race at the time that we decided to
move into the interferon field. We had a tremendous capacity to clone, to isolate DNA
from cells, and a great capacity to design and synthesize probes, but we didn t have any
depth in the interferon field. The whole race was won when a scientist from Genentech
attended a meeting, and he copied down the first four amino acids of fibroblast interferon
which were flashed on a screen by one of the scientists who was working in interferon in
Japan. With that information, we were immediately jumping ahead of the competition,
because we were immediately synthesizing the DNA and giving the molecular biologists
the unique tools to go out and fish out the gene.
Hughes: Was that a slip on the part of the presenting scientist?
Crea: In retrospect, the presenting scientist will probably never forgive himself. But at that time
nobody really had perceived the powerful technology machinery that we had put together
at Genentech. It wasn t until later that it became apparent that a small piece of
information but crucial piece of information can start a snowball effect if you have
the technology to turn that bit of information into a unique strategy that nobody else can
adopt. So that will give you an unfair advantage with respect to the competition. We
played that very well. That s why Genentech was able to accomplish so much in the first
few years of its activity.
58
Hughes: So, going to meetings and symposia was an important part of the job?
Crea: It was. It was as important as anything else. Again, having in a company a couple dozen
scientists with diversified skills didn t mean that we had the depth to be the experts in
every field that we were getting involved in. Actually, it wasn t realistic to expect that
such a group of skilled people could be also the key scientists in different disciplines,
such as virology, immunology, et cetera. It was impossible. So, for us, it was either use
the tools for achieving the synthesis and expression of the protein and then dig into the
biology and the more medical aspect by working with experts in the field, or looking for
the experts, like Peter Seeburg and Axel Ullrich, and try and attract them to Genentech so
that they could bring not only the skill set but also the expertise that they accumulated in
many years of work.
Hughes: Now, those two and originally John Shine was supposed to come as well didn t say
"Yes" immediately to Swanson s offer. Do you remember that being a concern?
Crea: Again, we were not surprised by this set of events. Number one, because we knew that
the people we were trying to attract were leaders in the field. We knew that people like
Axel Ullrich and Seeburg and others had many options to evaluate, not only in academia
but also in other companies, in a competitive situation. So, I wasn t surprised that there
wasn t an immediate enthusiastic response. It was part of the growing pains of getting
the best and making room for these prima donnas to move in with necessary support. The
company on the other side couldn t support exponential growth. It wasn t realistic to
grow double or triple the number of people in a very short time. It was part of the
anticipated growing stage that some people would join early on; some people would take
some time; some people would even join and leave the company. In my case, I had
people who didn t want to join and people who joined the company and turned out to be
not the right people, or they couldn t stand the pressure. The important thing was that we
had a very aggressive recruiting policy.
Hughes: Who was largely responsible for the recruiting? Anybody who had a connection?
Crea: There is no doubt in my mind that all of the push was coming from Bob Swanson, and
whether there was an influence by Boyer and Perkins, I would say most likely. Really,
the true vision was still coming from Swanson and some of the early scientists in trying to
anticipate the additional requirements the company had as we were building from the
ground up. Bob Swanson was connected with MIT, and he had several consultants
aboard from MIT. Also, early on, the company hired some specific people in human
resources to facilitate the screening of resumes coming from all over the country of
scientists who wanted to join the company. We had ads also in magazines like Science
and Nature. As I said, Genentech was in the press almost on a monthly basis, if not on a
weekly basis. We were really building our reputation by very qualified scientific papers,
participation in meetings and symposia, by promotion through magazine articles written
by science writers, analyst reports. So, there was really a slew of printed information on
Genentech. It was quickly becoming a reference point in the scientific world for a
number of scientists that wanted to come to the El Dorado of science in joining
Genentech.
Hughes: By the time you had arrived in the fall of 1 978, was there a publication policy in place?
59
Crea: Yes, there was a publication policy always in place from the early days of City of Hope,
as far as I remember. The policy was that we should publish as if we were in academia,
with only the provision that if what we were going to publish represented intellectual
property, we wanted to make sure that we first filed for patent. Then we disclosed the
information to the public. That was the only requirement that we get the release by the
key scientific staff and the legal department before we published a paper.
Hughes: Would that mean that a Tom Kiley, for example, would review drafts of papers destined
for publication?
Crea: Yes, and sign a release.
Hughes: Might he suggest that certain things be omitted or stated differently?
Crea: No doubt about it. But more than anything else, he would look at the content from an
intellectual property perspective. If there was something that we didn t include in the
patent, or even if we didn t file for a patent, he would make sure that all the proprietary
information would be the object of patent application prior to public disclosure.
Hughes: What about presentations?
Crea: Also, we had an internal committee to sign on presentations and publications because, as
I said, we wanted to keep the quality of the publications really high. So the scientists
were reviewing the papers and signing off on the quality of the science. The legal
department would review the paper and sign off on the protection of intellectual property.
It was a good system that I think is very much adopted by the biotech industry. The
quality of the publications was key for attracting good scientists into Genentech. The fact
that we published in Nature and Science and PNAS [Proceedings of the National
Academy of Sciences}, the most prestigious journals in the world, was already a sign that
we weren t going to compromise or cut corners with the quality of the science.
Hughes: Did you feel that the paper that came out was comparable to what your experience had
been in academia?
Crea: No doubt about it, even better. Again, the people who were writing papers were the same
people that were writing papers in academia. There was no limitation on the amount of
details to support an experiment. On the other side, we had to prove to the reviewers that
we were telling the truth. Eventually we had to provide even more details than anybody
else because we were breaking new ground, and as such we were the first to crack certain
experiments, certain techniques. So we had to be very detailed.
Hughes: Do you think that it made any difference to the reviewers that the authors came from
industry? Would, perhaps, their standard for approval have been any higher?
Crea: I don t think so. I don t think that there was a different way of looking at the publications
by the referees or reviewers. I believe that there could have been, in some case, referees
who argued, and sometimes even rejected our papers, based on a wrong perspective. For
sure, in my case, it happened a couple of times.
Hughes: Did it?
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Crea: Yes, I was very annoyed by reading the comments on some of the publications produced.
I thought at that time some were completely off the wall, and I couldn t understand
whether it was professional jealousy or people didn t understand what we were trying to
do. I can t specifically say if it was related to the fact that we were working for a private
company or more of the same game that is played whether you are in industry or
academia. My feeling is the latter. You always compete with the referees one way or the
another. You have to go the extra yard sometimes to explain or convince that what you
have produced is valid and of high quality and has to be published. Therefore their
criticism is not appropriate.
Hughes: All right, a little bit now about the business aspect. I understand that was not your sphere,
particularly. But in a small company you must have had some awareness. Putting it
simplistically, is it accurate to describe the three phases of Genentech s earliest business
development as, one, contract research and development, two, licensing products to other
companies, and three, a FIPCO [Fully Integrated Pharmaceutical Company], aiming to
produce every step of the production process within Genentech?
Crea: Well, from a business standpoint, the events at Genentech, as in any other small
company, were dictated mainly by the ability of raising money. Your bank account
allows you to step on the gas or slow down. What you have in mind is very much sobered
by reality, which is that you can t do everything, [laughter]
So, thinking of Genentech and what happened in the early days, after human insulin, the
company was very smart to raise private capital. That was a very important milestone.
The relationship with Eli Lilly didn t solve the financial needs of Genentech. Ibelieve
that it was more a validation that Bob Swanson and the other board members created for
the company validation by a big pharmaceutical company. But in terms of cash
flowing into the bank account, it was very modest.
Hughes: Do you mean that the flow was so modest that it didn t necessarily cover the cost of the
insulin project?
Crea: I don t know exactly the details, but I wouldn t be surprised, because I learned,
secondhand, of course, that there was a $500,000 license fee, and the rest was from
milestones and royalties. $500,000 wouldn t even have covered my budget. I imagine
that might have been a big struggle in Bob Swanson s mind, because he was probably
caught between the urgency to validate the approach that the company had taken and the
new technology in this new industry, and at the same time raise enough cash so that he
didn t have to dilute all of the investors with venture capital money. So, in retrospect, Eli
Lilly was a major event, but the immediate impact was more in public relations than in
the financials of the company.
After we had signed with Eli Lilly, there was a successful financing for Genentech in that
the company was able to raise money from Lubrizol, which was $10,000,000, something
like that, and other private investors. That was our first serious financing. Not only that,
but after Eli Lilly embraced the insulin program at Genentech, immediately the doors
opened to go talk to other big players like Hoffmann-La Roche and Griinenthal and other
pharmaceutical companies. Once we got the money form Lubrizol, the company really
started building in a more frenzied way, in anticipation, I assume, of bigger financing
through a public offering. It was a groundbreaking event. For the scientists, the message
61
was clear: the more we continued maintaining leadership in the industry, the more people
would be interested in investing in the company. But we scientists very seldom had a role
in raising money from private investors. It was more Swanson and Boyer handling that
behind the scenes.
Hughes: Was that system all right with you?
Crea: Oh, yes, I was very happy not to get involved in tedious business discussions or even
presentations. By then, we had elected a representative on the scientific stuff to play that
role, just in case that was necessary. So we had a director of research who was formally in
charge of presenting to investors, presenting in meetings, when it came down to selling
the science.
Hughes: By the late 1970s, maybe into the eighties, one could deduce that Genentech was
following the money. By that I mean, the company s application of these new
technologies was in a number of fields Pharmaceuticals, agriculture, vaccines. Was it
because of a desperate need for money that wherever you found a company that was
willing to support a project Swanson went for it?
Crea: [pause] No, I don t think so.
##
Crea: One reason was, Genentech wanted to be accepted as the leader of this new industry; and
two, to convince the pharmaceutical industry or any other industry which had business
related to biology food, agriculture that recombinant DNA was indeed a real
technology and not just a fluke. So, even after insulin, after those fifteen minutes of
fame, we had to face the reality that not everybody was jumping up and down, saluting
this as the birth of a new industry. Everybody was kind of skeptical about the potential of
the industry. For sure, the challenge was, "Well, you did this [insulin], maybe you got
lucky. But show me what you can do next." I am not surprised.
But maybe that s the nature of the beast when you come up with something
fundamentally and profoundly revolutionary. Everybody could dream about the
incredible number of applications. Early on, it wasn t difficult to imagine what one could
do: plants that don t need fertilizers, cars that doesn t need gasoline, because now we
have the bugs bacteria producing products. You can extend the application in an almost
unlimited fashion. The reality was that everyboby was asking, "What is it that is going to
be a blockbuster? What is it that is going to turn Genentech and the industry into
something real that the investor will believe?" It wasn t easy because initially the
applications of biotechnology were essentially focused on producing proteins, not on
curing cancer or changing the make-up of malignant cells and things like that. Ninety-
nine percent of the foreseeable applications of biotechnology were proteins which could
now be produced in bacteria. The perceived limitation was, maybe there will only be a
subset of proteins that can be produced in this way because other proteins will be so
complicated; other proteins will be glycosylated; the structure of other protein structure
will be so difficult from a three-dimensional standpoint that bacteria will never be able to
produce them.
Hughes: Well, that became true.
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Crea: Yes, that s to say that we were planning ahead in this overall scrutiny and skepticism that
this was the answer to the needs of industry and medicine as well. So, in a way, we had to
be opportunistic and grab whatever we could to support the growth of the company to
take the technology to the next stage of maturation, the next stage of demonstration. I
think that it worked out well that Genentech found a group of private investors who
decided to invest in the company, and give the company those two or three years of
financial latitude to build upon its skill set and produce a number of interesting proteins
for commercialization.
One of the happy choices that the company made early on was the selection of human
growth hormone. I think that that was no doubt a home run. But initially we didn t have
a sense of the business for human growth hormone. As a matter of fact we were looking
at bovine growth hormone as a moneymaker, because bovine growth hormone would
have had an application in cattle, meat, and milk production. We didn t know how
extensively human growth hormone would be used in medicine.
Hughes: Without the prospect of making bovine growth hormone, would the whole growth
hormone project never have seen the light of day? It wasn t particularly obvious that the
market was going to be very big for human growth hormone.
Crea: You are absolutely right. There was a big push in finding proteins that could be sold to
the market, and it wasn t human growth hormone that was going to generate millions and
millions. So bovine growth hormone played for a while the role of driving focus and
effort for commercialization. It came later that human growth hormone became so
important. But I don t want to say that if it wasn t for bovine growth hormone, we didn t
have a human growth hormone, because human growth hormone was one of the most
characterized human proteins in biology and physiology. So there was a lot of interest
from a biology point of view or medical point of view to understand the role of growth
hormone in diseases, in maintaining healthy growth, just for overall metabolism, cellular
metabolism.
Hughes: Was that body of knowledge in place by the late seventies?
Crea: Yes, there was a lot of interest around the function of the hypothalamus, the pituitary
gland. Let s not forget that already there was at least one company, in Europe, which was
selling human growth hormone for medical application. That was Serono.
Hughes: Wasn t Kabi also?
Crea: Kabi was also another one. These companies were purifying the hormone from the
glands of dead people. We didn t know in detail how big the market was going to be.
But for Genentech at that time, it was sufficient to identify proteins for which the industry
had an interest maybe a mature interest like in the case of insulin, or an incipient
interest like Serono and Kabi for human growth hormone. A lot of science was already
known about the hormonal pathways. But the struggle was having a sufficient amount of
pure material to develop medical applications, and that was the way I think that
Genentech, in the early phase, played an important role.
63
Hughes: How aware were you all during these early years that Genentech was a model for how
new cutting-edge technology could be applied? Was there any realization that you were
setting precedents?
Crea: No doubt that we were all aware that we were a cutting-edge company from a technology
standpoint. That was beyond question. What wasn t clear was whether the company was
going to fulfill its vision of becoming a fully integrated pharmaceutical company. That
was a new language for scientists.
Hughes: I bet.
Crea: And when Swanson and the board started positioning Genentech to become a
pharmaceutical company, I must confess not everyone was jumping up and down,
because we didn t know the implications.
Hughes: Do you think it was a bit premature to be doing that?
Crea: I thought that it was ambitious, but what did we have to lose? From our standpoint, the
fact that we had a leader, Bob Swanson, setting up new precedents and conveying the big
vision of becoming a big player in the industry was okay. It was confirming that we had
produced such an incredible set of discoveries that eventually could support the growth of
a pharmaceutical company. But nobody, including probably Swanson, knew what it
meant in detail. We had to go through a number of growing pains in learning what
development means. I m talking about process scaling up, large-scale production,
preclinical and clinical development. Nobody in the organization in the early eighties
was talking that language, letting aside whether we had the depth to build.
Hughes: You were getting a little exposure through Eli Lilly. Scale up was largely their
responsibility, wasn t it, for obvious reasons: Genentech couldn t do it.
Crea: That is correct. I remember that insulin gave us the first opportunity to even talk
internally about manufacturing issues, because it wasn t our job to solve those problems
or even deal with those problems. But eventually they became our problems because if
you have a sound approach at the cellular level or bacteria level, then it is a lot easier to
scale-up. But again, for us it was learning a new language, absorbing a new set of
information. With the interferon projects, we started digging into the biology. That was
the time we hired Dr. Noel Stebbing, from the U.K. to bring some knowledge of the
biology of the molecules that we were pursuing.
Hughes: What was his background?
Crea: He was a scientist trained in the U.K. and he was I m blanking right now.
Hughes: He was brought in to cover Genentech s lack of expertise in biology.
Crea: Yes, correct. He was essentially there to fill the gap between manufacturing protein and
understanding what the protein does at the cellar level and animal level. He was the first
at Genentech who set up collaborations with SRI [Stanford Research Institute] to test
some of our proteins in animals and design some animal experiments and then build upon
that experience to interface with the pharmaceutical companies. That tells you the degree
64
of knowledge that the company had or had not. It was a constant looking ahead into the
future and trying to understand what was necessary for us to build a pipeline.
Hughes : Did Stebbing do that j ob well?
Crea: I think that for a while he did. It is difficult in my opinion to judge what Noel did or did
not do in the company. For sure he managed to bring a different culture and set up a
number of collaborations with outside collaborators to test hypotheses to find out more
about the activity, the potency, toxicity mechanism of some of these new proteins. In the
end, I know that he left Genentech to go and work for Amgen. He became the VP of
research for Amgen. I don t know what motivated him to leave. I think that by that time
I was already gone actually for sure, because I was the first key player to leave the
company. There was a tremendous pressure to fit different roles and very often multiple
roles for key scientists at Genentech. In that respect, there were people who grew well
under that philosophy, and there were people who felt tremendous pressure and
sometimes couldn t stand the pressure and they left. As the company grew from a half-a-
dozen people to many hundreds of people, communication became an issue and became
more problematic among the members of the original team.
In my particular case, I was getting more and more isolated from the downstream
development, and even the molecular biology was becoming so diversified and complex
that it was difficult to participate with the designers of new experiments. It was
becoming more polarized, more under the direction of one or a few people, so the
company was in a way growing vertically. The science was also diversifying and
becoming more the contribution of many other people coming with a different
background. I didn t like it. I felt that we were losing something. But in retrospect, it is
part of the company s growing stage. I was getting more and more involved in the
bureaucratic aspects of running a department with a dozen people. Very little time for
brainstorming and collaborations, a more territorial attitude things that eventually
contributed to identified leaders in specific fields who took advantage rightly so of
the infrastructure that had been created at Genentech. We became focused more on the
specialty rather than the synergy.
Hughes: About what time was this beginning to happen?
Crea: I would say 1981, 1 982. I left at the end of 1 98 1 , so already in a previous year or two, we
experienced a lot of growth. Every time we were adding scientists, it became more
difficult to follow everything that was going on in the organization.
Hughes: What about your own field? When did DNA synthesizers come in, and what impact did
they have?
Crea: Well, the real breakthrough in the DNA synthesizer came in the mid-eighties. But
already in the early eighties, we were working, and other people were working as well, on
the gene machine. There was a new chemistry being developed to produce the DNA
faster, coming from Marvin Caruthers s lab, in Colorado. It wasn t clear what was
profoundly new and what was mimicry. For us, it wasn t smart to switch to something
that we didn t know and we didn t control, while we were milking the cow which we
knew well and we controlled.
65
In the end, we saw the birth of a number of companies pursuing synthetic DNA. We saw
a sophisticated machine coming to the market and then disappearing. It wasn t just the
machine itself; it was more the understanding and the control of the chemistry that was
going to be used by a machine. Our group attempted to automate the chemistry in
collaboration with Waters Associates, in Massachussets. Waters provided the
instrumentation, an HPLC, which was turned into an automatic synthesizer, having that
cellulose as a solid support. It was more breaking ground and at the same time we were
producing quite a bit to support the effort in molecular biology. Ultimately, the DNA
machine became a real opportunity for companies. As I said, it became an alternative to
the manual synthesis in the laboratory only in the mid- to late eighties. From my
standpoint, it was keeping an eye on the progress in chemistry, but at the same time trying
to focus on the applications that we could pursue by having at our disposal so much
synthetic DNA.
That coincided with the beginning of my uneasiness with the company. I wasn t any
longer excited about playing the number game how many oligos could you produce in a
week? That was something that could only go up in time. I was interested in all of the
interesting new concepts that were being developed with the use of DNA. For instance,
the strength of promotors, the interaction between DNA and enzymes. These are all
issues and projects that ultimately turned out to be very important from the manufacturing
standpoint. I was intrigued by them. I can make DNA. I can write biochemical software.
What can I do with this ability to write molecular software in terms of learning how to
play more efficiently with bacteria or human cells or other cells? My interest started
shifting from the pure assembly of genes to the use of DNA for molecular biology. Little
by little, in our laboratory we were not only synthesizing the DNA; we were also making
genes; we were cloning genes. So the definition of chemistry was becoming more and
more gray, at least in my mind. But that wasn t easy to be accepted by the other prima
donnas.
Hughes: Because they felt that you were encroaching on their territory?
Crea: Exactly. They felt a little bit intimidated or threatened. So, in the end, it was if I can t do
interesting work, I am not interested in doing routine; we can pass it on to somebody else.
Maybe I can go out and start developing my own systems. We at Genentech were one of
the leaders in DNA synthesis in the world. We could introduce restriction enzyme
sequences in your genes. We could design new sequences for promotors. We could
make all protein analogs by just mutagenesis. We could make artificial proteins, like
mini-proinsulin. These are all things that we did at Genentech probably for the first time.
We were opening up a world of applications, without going too far from what we were
doing every day, just by designing smart sequences.
Hughes: Were these extensions supported by the company?
Crea: To some extent, yes; to some extent they were perceived as being molecular biology
territory and none of my business. I worked with Peter Seeburg and a number of
molecular biologists at Genentech for optimizing a sequencing system in E. coli. I
worked with Herman DeBoer on developing new promotors for better translation of
messenger RNA. I worked with other scientists in designing protein analogs for better
performance, better activity, and even protein engineering. Really, I was smelling and
enjoying the flavor of the DNA applications. I didn t feel comfortable any longer being
66
left at the periphery of that excitement. The more I wanted to participate, the more I was
finding resistance by the so-called molecular biologists. So, in the end, I felt uneasy, and
I started dreaming of my own organization. That was the time I started thinking about
going out and leveraging upon my skills to help many other laboratories to get synthetic
DNA. I had a very good perception of how the increasing demand in the new industry
was going to support my business in synthetic DNA. In the last couple of years at
Genentech, I was working with dozens of outside laboratories in basic research. I was
providing primers and probes for interesting projects. I felt that as the synthetic DNA
gene machine was moving into the laboratory and therefore the DNA would become
available to many other laboratories, that I could facilitate that stage of development,
knowing that many laboratories in academia and industry were interested in the synthetic
DNA approach.
##
Crea: At Genentech, we had DNA chemistry, of which I was director; molecular biology,
which I think was either Goeddel or Herb Heyneker; then we had protein chemistry and
biochemistry, of which Mike Ross was the director; then we had biology, of which Noel
Stebbing was the director. We had elected Giuseppe Miozzari to represent all the
departments early on, as a scientific director, but Giuseppe left to join Ciba-Geigy some
time in 1 980 or 1981. That role I don t remember was filled by Dennis Kleid or Herb
Heyneker. But when I left in October of 1981, 1 think the company was recruiting a
scientific director, who eventually was David Martin.
Hughes: We skipped over the IPO, and I am curious as to how much this was a discussion point.
Was it something that Swanson was preparing you scientists for, or did he consider it his
own business domain and managed it in isolation?
Crea: It became clear once the company started raising money from private companies, from
private investors, that the stock now had a value. As a matter of fact, part of that private
transaction which brought Genentech millions of dollars from Lubrizol, I remember, gave
the scientists the possibility of liquidating some of their shares. Specifically, we were
told that we could sell up to ten percent of our holdings. For us, it was the first time that
apiece of paper was worth something. Some of us did. I believe at that time, the price
per share must have been something like three dollars. For us it was good money,
because you could put down a mortgage for buying a new house or a new car.
It became clear at that point that the Company s shares eventually were a tangible asset
for the early players and the new players. So, we started paying more attention to the
analysts review of Genentech. I remember very well that when the company put
together the first annual report the beautiful brochure in black and white with beautiful
pictures we had the perception that now we were getting ready for the public; we were
getting ready for the masses, the large audience. The annual report, dated 1980, featured
the company as unique in terms of people, accomplishments, milestones, and the
organization as well. It was presented as a very well-balanced organization to sustain
growth to become a pharmaceutical company. It was a clear message to the investment
community that we were growing by putting together integrated skills and this new set of
scientific information and looking forward at the end result of becoming a real business.
1980 was a clear milestone year for the company in that we were presented as a mature
organization ready to take off and become an integrated and successful business.
67
Hughes: Did you have any anticipation of the actual success of that IPO?
Crea: No, I don t think anybody was expecting it. The whole motion wasn t something that the
scientists got involved in; it was more Swanson s orchestration. If you would have taken
a snapshot at Genentech, you would have found that in the early eighties, everybody was
busy building his own kingdom a good positive aspect. There were a lot of races for
new molecules, exciting molecules interferons, proteolytic enzymes for blood, et
cetera. Now the race was for making drugs to save lives, not just for replacing proteins
that cannot easily be produced by an animal or by synthesis. The focus was more on,
"We can do something to save lives, such as curing heart attack, having an impact on
thrombolytic therapy, cancer." So really the motivation was now to build on the science
and add depth to the work that we had done early on. The business side was not our
problem; we trusted that we have a good management team; Bob was very good at
negotiating things; eventually we will succeed. But really, the lack of any business
experience among the scientists did not give us the perception of what was going to
happen with an IPO. We couldn t possibly imagine that on the first day of trading
Genentech stock was going to jump to $89 from $35. Yes, we were curious, anxious to
see whether we were going to succeed in getting public support, but not even in our
wildest expectations we anticipated that glorious splash in Wall Street.
Hughes: Do you think that Swanson had any inkling?
Crea: No, I don t think so. I don t think that anybody had that perception. One thing that I
remember was that the price of the shares was negotiated until the very last day, and I m
sure that Swanson was happy to get $35 a share. If he knew that the stock was going to
ninety, I m sure that he would have negotiated to at least fifty. It was very much a
surprise to everybody. It was a happy surprise.
Hughes: Do you remember exactly how you learned and where you were?
Crea: Yes, I remember there were moments of celebration, but it wasn t the same as the ones
that followed the human insulin experiment; it wasn t as genuine. It was more "Wow,
now we have become not only well known but also rich." It was a strange feeling, I must
say. On one side, of course, we were very ecstatic of the acceptance we had from the
public offering. But on the other side maybe it is part of human nature I knew that my
stock was worth X, but my colleague who was smarter than me and had more shares, now
had twice as much. And why? Wasn t I as important as the next guy? So it really started
getting into your mind from a different point, from the greedy financial point. Then you
start thinking "What alternatives do I have now that I have some financial latitude?" So,
it is really a different dynamic that suddenly you re worth a lot of money, and you don t
know whether your fortune it is going to go up or go down. It triggers a new series of
questions and anxious feelings.
I remember that I was coming back from a trip the day when the company went public.
I m not positive, but it could have been a trip to Los Angeles with Fred Middleton. We
were walking in the terminal of the San Francisco Airport and we saw the front page of
the San Francisco Chronicle with "Genentech," a big title. I was like,"Woo, something
happened today." We bought the newspaper and it was a beautiful article I believe it
was the afternoon edition which saluted the incredible financial exploit by Genentech
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on Wall Street. I bought a number of copies, because that was going to be a memento to
keep forever.
Hughes: So your new status as a public company didn t change your day-to-day activities?
Crea: No, it didn t because although we had stock it wasn t clear whether we could sell it. It
wasn t clear what were the restrictions. It wasn t an immediate money-in-the-pocket
situation. It was more a perception that we had built something valuable, that a lot of
people were finding themselves very wealthy, and that this was getting to be serious stuff.
Hughes: What about in terms of accountability? Was there any change in that regard?
Crea: No, because the administrative and financial machinery was well in place at Genentech to
provide the information required by SEC [Securities and Exchange Commission] filing,
investors relationship, public relations. The company had a number of skilled experts in-
house to deal with our new situation. What changed was the frequency of articles on
Genentech. There was a lot more interest in the company after that big splash. We saw
more and more articles by financial institutions, by analysts, by magazines like Business
Week, not just Science and Nature, et cetera. We also enjoyed being at the center of the
financial world. There were a number of articles published on the scientists as the
players. So that was a good reflection of what had changed.
##
69
[Interview 5: November 11, 2002] ##
Hughes: Today we ll discuss thymosin. This is one of the many projects at Genentech on which
you worked. Do you know something about the origins of the project?
Crea: Yes. Whatever I remember after twenty-plus years. Thymosin was our first project at
Genentech where we tried to take advantage of an early discovery in biology to mass-
produce a very interesting protein. The thymosin alpha- 1 was a protein which had been
discovered and studied by Dr. Goldstein Alan Goldstein, if I remember well.
Hughes: Yes, that s right.
Crea: We managed the project together with my colleagues at Genentech, especially Ron
Wetzel, who came from the laboratory of Dr. Dieter Soil to join my group in 1979. We
approached the scientific aspects of producing thymosin alpha- 1 with the benefit of the
support of Dr. Goldstein. He came to Genentech to tell us about this important discovery.
Hughes: You mean he initiated the contact?
Crea: He initiated the contact with the group. By then the biology of thymosin was being
uncovered, and there were a lot of good data indicating it might be an important protein
for mediating the immune system, [tape interruption]
This was an ideal project for us in that the protein wasn t that large only around thirty
amino acids, I believe. Therefore it was very approachable by our synthetic DNA
method, which had been successfully used for human insulin and other small proteins. So
we decided to embark on this project, and we started the design of the gene.
The early part of the project landed in my laboratory, and my people synthesized the
oligonucleotides which were necessary to get this job done. Again, the fact that Dr.
Wetzel was in my group and that he was coming from a laboratory where they had done a
lot of protein biochemistry was very important; our group had the chance not only to
produce the protein itself, but to purify and isolate and start verifying the biology and the
biological activity. So it was a good match and gave us also an opportunity to expand
outside the chemistry itself.
Hughes: Ron Wetzel eventually has his own laboratory doesn t he? Doesn t he become the protein
chemistry expert as opposed to an expert in DNA synthesis?
Crea: Yes, eventually; I think thymosin was indeed the opportunity for him to be at the
interface between our group and the protein biochemistry group. From that point on, he
did such a great job in taking the project throughout the synthetic steps and the cloning,
which was done by the molecular biology group, but he was supervising that activity.
Then he was leading the effort in protein purification, characterization; and he was
maintaining the relationship with Dr. Goldstein in studying the biological activity of the
recombinant protein. That became an important role for Ron as a project leader. We were
successful in completing that project, and Ron did a masterful job in taking the project
70
from A to Z. In that respect people started appreciating his role as a protein biochemist.
As the company started adding projects and people, and the biochemistry became an
essential step in the development of recombinant proteins, Ron was given the
responsibility to lead his own small group.
Hughes: Do you remember when that might have been?
Crea: I think it was around 1 980-8 1 . It was interesting because my group in DNA synthesis was
involved with a more and more streamlined process. We had now optimized the synthesis
and purification, so really the synthesis of oligonucleotides, per se, was becoming
routine to the extent that people could use DNA by simply filling out a form, passing it
to my people, and getting the DNA ready within a week or two. In that respect, it was a
lot more interesting to apply the use of synthetic DNA to interesting projects where the
end point was either an improvement in molecular biology a new discovery in
molecular biology or all the way through the protein expression and characterization.
I felt, myself, that having optimized the chemistry and having built the group, that it was
working sufficiently to support a very large number of projects. At Genentech, I was
losing a little bit of track of what was going on downstream because the use of DNA
quickly branched into all kinds of projects at Genentech. There was a use of probes for
fishing out messenger RNA: a use of primers for mutagenesis or for isolation of
messenger RNA or cDNA synthesis; there were synthetic genes; or other use of DNA for
modification of genetic elements, like promotors, terminators for plasmid construction,
and expression improvements.
So the DNA was readily available. Why not use it for everything, to take a lead in the
industry? In effect, I was extremely pleased by this fact that our group was supporting the
entire organization, but on the other side, I was becoming aware that I had to do
something new and different. Otherwise the risk of being a rum-key department would
have been very big, and Ron Wetzel, also, as an intelligent scientist, felt that his role in
the company could be more rewarding if he would take more responsibility for the
characterization of the protein. With Ron Wetzel, obviously Genentech was able also to
introduce some additional techniques and technologies as well. At that time the computer
modeling of proteins became an important tool for understanding the structure of protein
and trying to correlate structure to function. So in that respect, Ron was capable of
establishing relationships with leading groups in academia, such as UCSF, and bringing
into Genentech that modeling capacity.
With respect to my own interests, I had already branched into other activities for
chemistry. We were doing a number of additional projects which went beyond the
improvements of DNA chemistry as such. For instance, I was working in collaboration
with a group in Holland to study the function of small, modified nucleosides in the
activation of the interferon alpha expression. I was working with Dr. Noel Stebbing, head
of biology at Genentech, to develop some nucleoside and nucleotide analogs as supposed
anti-viral compounds. So we were already ahead with some interesting projects for small
molecules based on the DNA chemistry.
Hughes: Was this enough to keep you happy?
71
Crea: To some extent it was, in that I had a number of projects to pursue on my own, but on the
other side, I was too interested in the molecular biology, cell biology revolution. I was at
the very head of that revolutionary process. To some extent my group triggered the
unfolding of that revolution, and I was extremely excited about participating, especially
in the protein engineering in the designing of gene analogs, which could eventually lead
to protein analogs with improved properties. I had a feeling that we had now the
"software" readily available to direct bacteria in mammalian cells to produce designed
proteins, and that was an open world. It was unfolding, and I wanted to be part of it.
Hughes: Now did it take any particular effort for you and the people you were working with to
move from an emphasis on the nucleic acids to becoming protein chemists? You were
still chemists, I would think, with a capital "C," but what you were applying your
chemistry to began to shift, did it not?
Crea: No, actually it wasn t difficult for people like me to move across projects. Obviously the
intention wasn t to replace the so-called "experts."
For instance, in molecular biology, during my period at Genentech, there were
tremendous improvements in techniques and technologies. Obviously, you know, I
wasn t trying or pretending to replace the skilled molecular biologists in the laboratory.
But the big picture was different. The big picture was that you could, in effect, now you
had all the tools to program the protein production mechanism in the cell, control that
mechanism with bacteria or their cells, to the extent that you could design things in the
laboratory and generate a specific protein. It was a lot of power, because now you could
think of modification dictated by scientific evidence or intuition or structural-function
activity relationship.
So in a way, as a chemist, I could appreciate the function of a protein in its biological
activity. In other words, in the end each protein is different because of its structure. So if
the activity is due to a structure and you can control the structure and change the
structure, obviously it becomes very exciting to understand the fundamental rules of that
game and try really to generate an optimum protein with optimal biological activity for a
variety of medical and industrial applications So in that respect, it was more a decision
how to spend your time in the laboratory, whether to focus on the end point, or on the
middle point, or at the very beginning.
I had done my time, and paid my dues at the very beginning with the DNA chemistry.
Now I wanted to participate in the really tremendous opportunity that technology at the
DNA synthesis and molecular biology level had created for the ultimate output of the
protein itself. When you look at the structure of proteins and you look at the interactions
between proteins, it comes down to chemical interactions. So that, culturally, was very
close to what I was doing with the DNA. It was just shifting focus from DNA to proteins,
but from a chemical point of view, the rules are very, very much similar.
Hughes: Well, understandably, we diverted from thymosin. Do you want to say something more
about that?
Crea: Well, no. There is another part of my career, which obviously had influence on my
shifting from DNA into the proteins.
72
Early on, we had initiated a parallel project for the synthesis of proinsulin, and mini-
proinsulin. That was in 1978. At the same time, we were working to produce the synthetic
genes for the A- and B-chains. We were already thinking about a smart, unique
modification: how to shorten the length of the C-peptide, which is the peptide that in
nature holds the A-chain and B-chain together in a way that they can form disulfide
bridges. Then the C-peptide gets cleaved by enzymes, and you get the native insulin. But
even as early as 1978, we were talking about artificial modification of the C-peptide to
make it long enough to position the two chains (A and B) so that they could form the
disulfide bridge without having to go through this long chain that nature has adapted.
So in other words, we were trying to outsmart nature by modifying the size and the length
and the structure of a natural component so that artificially now, in bacteria, we could get
the same effect but with a much simpler strategy.
Hughes: So that was a refinement of the process, wasn t it? Somatostatin preceded insulin, but
that, if I m right, was just a matter of pasting the somatostatin gene onto a larger
molecule. It wasn t that you changed the gene per se.
Crea: Correct.
Hughes: So here you were, for commercial reasons, changing nature s design.
Crea: Correct. Yes, and again, it was scratching the surface of the numerous applications that
became immediately available to creative minds having synthetic DNA at their disposal.
Now you had a situation where you could impact on the industrial production of a protein
by changing, artificially, the length of a peptide. So that was very attractive.
When we started the mini-insulin project, in effect, we were opening up a new world of
applications which today is recognized as protein engineering. We were doing protein
engineering. Obviously, you know, many laboratories were thinking in a similar fashion.
But we were doing it while other people were still thinking about it because we had the
tools in hand.
Hughes: Now do you think from the start people had, well, people particularly at Genentech, had
the idea that what they would be attempting to do would be more than just duplicate
nature?
Crea: Yes, although, from a business standpoint, it was the first strong message that the
company was trying to convey to the industry and to the public. Here we are with a new
technology capable of reproducing what nature does, in a much easier, much cheaper
fashion to pass the benefit to the patients or to the consumers.
So the first message was, "We don t need any more very complex systems to produce
large quantities of human insulin for diabetes. We don t need to really harvest hundreds
and hundreds of kilos of human pituitary glands from cadavers to produce human growth
hormone. We don t need" to use another example "We don t need to grow thousands
and thousands of liters of media to isolate a little bit of interferon; now we can use
bacteria, which do the job in a soup essentially."
73
Hughes: The point I ve taken for granted is that recombinant DNA and the other genetic
technologies were going to do things faster or more efficiently than had been done using
more traditional techniques. But the idea that hadn t occurred to me before until this
conversation is, you don t just duplicate the insulin molecule, you tailor it through an
industrial process to make it more efficient, or more productive, or whatever it is. Was
that idea always implicit in the biotech endeavor?
Crea: It s fascinating, as things become obvious when you have the tools, and maybe the first
time, you don t rationalize, then you do rationalize and because it s so obvious, you don t
think that that was the first time. You don t think that you might have been the first in the
world.
I think that was, in a way, the origin of protein engineering. In other words, with a
synthetic DNA, with the use of probes, early on we demonstrated that you can change a
gene very easily. So you can take a natural gene and you can design a complementary
piece of DNA with a one-base mismatch to change one codon in your gene, and
obviously, by changing one codon, if the codon is responsible for a specific amino acid,
once you put the system back into the cell, you re going to get an analog. It was like, "So
what? We can do it." It s almost a natural progression.
But in retrospect, you know, that was the birth of a new, powerful technology, which is
today recognized as protein engineering. I m not saying that Genentech invented that;
what I m saying is that what we were doing, we were doing very early. We were the
operators. We were thinking and doing much earlier than anybody else.
The insulin was a first example, but when we started working on GEP, the gastrointestinal
peptide, there was a clear intention to generate peptide analogs, to identify whether there
was one specific peptide that could be more active than a natural one. So that was, again,
a specific project to change the structure of peptides to identify something that even
nature had evolved, and anticipate that kind of evolution in the laboratory to be able to
discover something which works better from a health care application.
We did it. We generated a number of analogs, but very often, when you deal with
technologies at an early stage, you stumble into unanticipated, time-consuming steps
which might discourage you from taking full advantage of that technology until another
piece of technology helps streamline that process. I think that was the reality. In other
words, if making genes, and making gene modifications in gene analogs was easy, it
wasn t so easy to take the gene into the bacteria and then express and purify the protein in
quantity such that you could study very quickly and very easily in the laboratory to say,
"Yes, this is a better one." Or, "No, it s not. Let s go back and redo it." Obviously, the
tools were there, but the underlying capacity to understand which change in the protein,
and why, still remains a big challenge in biotechnology and biology as well. So it is
today, twenty-five years after we have developed the tools. So again, the creativity, in a
way, often gets tempered by what you can do in the laboratory by the cost, speed, of
going through the motions; if it is very lengthy and expensive, obviously, you can t do it
many times.
But, yes, the use of DNA eventually became almost universal for these kinds of studies
on proteins. That s where, also, the modeling became important. Having a lot of proteins
now available from recombinant DNA, and having the possibility to modify those
74
proteins we needed as a community to develop some tools to direct our manipulations,
our changes, in a very intelligent fashion, rather than in a random way. The computer
modeling was a first attempt to visualize the changes based on mathematical calculations.
What happened if you replaced now one amino acid or a few amino acids with others,
what happens to the structure of the protein, and what kind information can you gather
from that new structure as related to its biological activity?
Hughes: Shall we pick up the thymosin story again? [Laughter]
Crea: Well, the thymosin in my mind is a short-fuse program. We verify that we can do it, we
go once more through the motion of making a gene, cloning the gene, producing the
proteins and let the expert isolate the proteins, identify the activity, and then take it to
the next step, which was the pre-clinical experience.
As director of DNA chemistry, you can follow your own babies to a certain point and
then you have to let other people take over. So for me, it was, "Okay, this is the end of
thymosin." We finished our job. Dr. Wetzel is doing a fantastic job in taking it all the way
to the laboratory of Dr. Goldstein so that he can verify the biology and ultimately come
back to us with some answers: whether or not this protein is ever going to be a therapeutic
agent for the benefit of sick people, people with some diseases.
But at that point, things get too far beyond what we do daily, and if you decide to jump on
one project, then you lose the opportunity to do the others. So it s always a challenge to
prioritize projects in the laboratory.
Hughes: Do you mean by that you believe there could have been therapeutic potential in thymosin
if Genentech had chosen to put more emphasis on it?
Crea: No, I think that Genentech as a company had to make some choices based upon business
opportunities and technology limitations as well. While we were working on thymosin-
alpha 1, the interferons as a class of molecules were being discovered, and there was a lot
of excitement around interferons as potential molecules for the cure of cancer. Now they
are major drugs for several diseases. I believe when you are in a position to "cherry-pick"
your projects, you start developing plans, and often the plans which Genentech did have
to keep in-house were several
##
Crea: Some of these projects at that certain time might not be as valuable. I believe that
thymosin was at its early infancy from a biology standpoint. We didn t know too much,
and it was difficult to understand the specific activity or the range of activities. So I
believe that the decision to prioritize other exciting projects came easy for Genentech.
Hughes: Does that reflect the undeveloped state of immunology around 1980, the late 1970s?
Crea: Yes, no doubt about it. Thymosin might be a good example. We have other examples, for
instance, growth factors. We knew that they were important proteins because they were
discovered to mediate some important biological mechanisms. But we didn t understand
the full importance until years later. We are still digging in to understand the full
significance from a physiology standpoint.
75
So it s true. Very often when you are ahead of your time you are capable of making
something, but there is no science that supports the use of a specific molecule or protein
to justify the investment of hundreds of millions of dollars in clinical development. If the
science doesn t support the development of the protein, you re taking a big risk because
you might develop protein as a therapeutic for the wrong application, and then find out
that it doesn t work. It doesn t mean that it doesn t work in the body; it means that for that
specific application, you won t get any results. But maybe later on the same protein is
discovered as an important therapeutic for something else.
Hughes: I believe it was you who said that the importance of introducing into Genentech a
stronger biological interest became apparent. I wondered what the thinking was. Swanson
perhaps thought, "Well, all I need is chemical synthesis and people who can clone
genes."
Crea: I believe that every time a private organization has to depend on somebody else, it puts
itself in a very vulnerable position. I think that the thymosin might be just the example of
what I m talking about. We were doing something for an external laboratory, so we didn t
have any control. We were providing the protein the active material but then it was
totally out of our control, totally in the hands of somebody else in another laboratory.
Every time you do that, you know, obviously you feel yourself taking a lot of risks
because you don t have direct control. I think that might have been one of the reasons that
prompted Bob Swanson to establish a stronger biology department.
To the extent that we can understand proteins, their function, their activity internally, and
we can verify with our own experiments animal- or cell-based the biological if not the
pharmacological activity of a protein, then we have total control. Then we can make an
intelligent decision whether or not we should go for a cure of cancer, or cure a
neurological disease or diabetes type 2, et cetera.
Stebbing was the first at Genentech who established the initial animal study verification
in support of some of the projects that that company was pursuing, like interferons for
instance, and growth hormone. So it was a way to build the infrastructure of the company
such that we could become stronger, independent, fully integrated, and less dependent on
other people at other laboratories.
Hughes: So Swanson wasn t difficult? He came around to that idea without much persuasion?
Crea: No, I think it was recognized by everybody at that time that the more we can add
internally the better off we are. That in a way is the blueprint for the growth of
Genentech. You can see now where Swanson and the board were driving in the early
stage. They were trying to identify the downstream disciplines and skills which
eventually would be internalized to become more and more a well-rounded business and
technological powerhouse; to be self-sufficient and not to be dependent on other
companies or other laboratories.
Hughes: Now in the earliest days, my memory is that there were only three people on the board
Swanson, Boyer, and Perkins. Boyer was the only one on the board who knew the
science. Did he advise that Genentech needed to acquire biological knowledge within the
company?
76
Crea: I believe that in part came from Boyer, but don t forget that there was a constant dialogue
between the scientists and Bob Swanson on the different projects, almost on a daily basis
and for sure on a weekly basis. So there was this constant dynamic in understanding what
else the project needed in order to achieve success. I believe that the majority of the
visionary position came from Bob Swanson also because he had the luxury to interact
with a lot of creative minds who were identifying on a daily basis the next new, important
step.
Hughes: Also at some stage certain scientists began to make presentations to the board, did they
not?
Crea: Yes, absolutely.
Hughes: Did you ever do that?
Crea: No, I never did it other than very early. I remember I was part of the team, together with
Boyer and Swanson, which went to promote the interferon project with Hoffmann-La
Roche. But we had a scientist designated to represent all the research departments. I think
it was Dr. Miozzari. And it was up to Miozzari to convey to the board the depth of our
technology and the range of projects we were pursuing; to keep everybody abreast with
the progress.
Hughes: When a board meeting was coming up, do you remember if Miozzari tended to take more
note of what the scientists might feel? Would he come around and collect opinions?
Crea: Absolutely. Miozzari was a very intelligent person who had a lot of good chemistry in
interacting with all the key scientists. So he was definitely representing not just himself,
but the small community of the scientists at Genentech. [tape interruption]
A major resource available to Swanson, to the board, was a range of good consultants
with different backgrounds coming to Genentech. Obviously, you know, you hire
consultants to hear what s going on out there. What is it the company needs to do well in
its projects? What kinds of skills did we need to bring in-house to accomplish that?
Hughes: Do you remember who any of those people were and what they were consulting about?
Crea: I remember one for sure, and that was Professor George M. Whitesides from MIT. He
was a great resource to the chemistry department, to the protein biochemistry department.
Professor Whitesides is a recognized authority in organic chemistry and protein
biochemistry. So I think we got a lot from him. He was or still is, I guess, MIT emeritus
professor, and he was one of the teachers of Swanson in chemistry. He knows extremely
well what s going on in the field of science and medicine as well. So I think he was very
instrumental early on, but I m sure that there were a number of consultants. I left the
company in 1 982, so I imagine that from that time on a number of people came to work as
consultants.
Hughes: Well, should we proceed to proinsulin?
Crea: Yes, the proinsulin was an attempt to simplify the downstream assembly of the insulin
molecule. You know, insulin is made of two chains, A-chain and B-chain. They need to
77
align properly in the cell to form a disulfide bridge. There are two intracellular disulfide
bridges that require that the two chains come together at a distance where the disulfide
bond can be formed.
The reason why we started the proinsulin project came as a result of the technology
limitation of making A-chain and B-chain separately in bacteria, and then trying to
reconstitute the molecule in vitro. That is a very difficult, time-consuming, and especially
inefficient kind of process. The idea was, well, why don t we try to mimic nature and try
to do exactly what a human cell does except we tried to do it in part in bacteria. We
provided the enzyme so that the bacteria didn t have to clip the C-chain after the A and B
go together.
The proinsulin was, again, taking the A- and B-genes that we synthesized early on,
modifying the end of one and the beginning of the other one to fuse the two genes to the
C-chain, which was also synthesized chemically, and doing it again, going through the
exercise over and over. This time it was a longer gene which included the B-chain, C-
chain, and A-chain, in that order, and to express in E. coli and purify the precursor and
then let the precursor fold outside the cell as it would in the cell. After the refolding is
complete, come with an enzyme that clips the C-peptide and restores the insulin.
It s interesting because this project came as a result of our early collaboration with Eli
Lilly. Eli Lilly took over the scale-up of the human insulin to produce a commercial
product and realized early on that it wouldn t have worked with the B-chain and A-chain
separately. We did it at the laboratory level, and the best we did was to produce one
milligram of human insulin. But, that was plenty to validate the concept, but it wasn t
obviously sufficient
Hughes: For commercial purposes.
Crea: So a deep analysis of the technology developed at Genentech obviously resulted in going
back to the drawing board and redesigning the strategy, which we did.
Hughes: Who was directly involved in the redesign?
Crea: Well the redesign was extremely straightforward because there was really not much of a
brain in order to do that. Again, that was a simple situation where we had to reproduce,
exactly, the amino acid sequence of human insulin, and modify the 3-prime [3 1 ] end of
one gene to accommodate the beginning of another one, and then attach to the second
gene, a third one. It was just a simple replacement of DNA to come up with a longer gene.
So that was no big deal. There was no new science at that point. It was just redesigning
based on a genetic requirement, more than a protein and peptide requirement. So that was
a small project.
Hughes: And where does Eli Lilly fit into this? Because as I understand it, they were given two
different types of clones? One was with this proinsulin approach, and what else? Weren t
there eventually two methods that Eli Lilly was using and then began to favor one over
the other?
Crea: Well, I don t know exactly how many constructs were produced. But for sure Eli Lilly
became our industrial partner for scaling up, and industrial development of insulin had
78
the job to mass-produce the protein. So I imagine the scientists that Eli Lilly started with
took the clones and bacteria which we had produced in 1978, and produced separately the
A-chain and B-chain and tried to assemble that way the human insulin.
What we learned early on around 1979 was that it wasn t efficient to produce
separately A and B. That s when we decided to do the proinsulin, to try a different
alternative. I m sure that having the mini-proinsulin in hand, we might have also given
Eli Lilly this alternative construct to try. Again, it was like "Let s build another model
and see whether it works." Ultimately, one of them proinsulin must have worked
because that was the one that was selected by Lilly for scale up. While we were working
on other things, one day we learned that insulin was ready to be registered and approved
by FDA.
Hughes: That was pretty exciting!
Crea: That was a pretty exciting time. I still keep one of the insulin called humulin vials
embedded in glass as a memento of the historical moment. It was the first product made
by scientists in the laboratory with recombinant DNA technology, which was introduced
in the marketplace.
Hughes: Did you have any direct contact with the Lilly people?
Crea: Only at the very beginning. But again, it was more the protein people interacting. Michael
Ross was a head of that department, so Mike and his people were the interface with Eli
Lilly. That was an interesting situation. I m sure that a lot of people at Genentech must
have shared this sense of letting somebody take the ball and run. We are a team, and each
player has a function. I m defense, somebody s a quarterback, and somebody s in charge
for scoring.
It was interesting how the protein people the protein biochemists in essence, had the
great job of taking the ball, taking the protein ahead, and going ahead to score. Because
that excitement of interacting with the ultimate user or manufacture was never shared
with people who did the early job. It was more in the hands of the people who would
better interface with the scientists of the other company.
Hughes: Was that hard to take?
Crea: Not really, no. To the extent that it didn t become a territorial fight. To the extent that
there was an overall recognition that it was a team effort. It became less pleasant as the
company grew. You can imagine at Genentech itself maybe thirty people at one time
were involved in the same project, but only one or two had the luxury to come back with
the glory of having interfaced with the ultimate scientist or company, which made the
final breakthrough.
Hughes: And that tended to be the cloners in the early days, did it not?
Crea: In the early days, it was the cloners, because there was a lot of interaction well, for a
number of reasons. The cloning and the expression of certain proteins was still not a
trivial task. So being able to be the first to clone and express a protein like interferon, or
human growth hormone, or tPA was still a front-page event. Later on when cloning and
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expression became almost a routine, obviously, the focus shifted to the biology, to the
first experiments to demonstrate that the protein produced in E. coli or mammalian cells
did indeed something exciting in animals or even in cell systems in the laboratory.
Of course, then later on, the focus shifted to the clinical development. In other words, to
the ultimate answer, "Is it going to work in the hospital to help people who need it?" Or,
"It has been a great attempt, but nothing else but a great attempt." So you can see how as
the science evolves and the technology matures and becomes readily accessible, you lose
the halo of hero. You become a normal mortal. I thought that there was a lot of
excitement downstream for proteins and protein engineering and then to be only a
common mortal at Genentech . [Laughs] So I wanted to do it outside of Genentech; that
was one of the reasons I left.
Hughes: Shall we discuss the interferons? The interferons, of course, were in no way discovered
by the genetic engineers. There had been various people for many years
Crea: Many years earlier.
Hughes: trying to develop them as therapeutic agents. My understanding is that one of the big
drawbacks was that they were present in very small amounts. And because they were
present in very small amounts, their characterization was not adequate?
Crea: It was very difficult. People detected the presence in the cell of interferons and people
knew they were proteins, but they were such a small quantity that isolating even
milligrams of these molecules was really a huge undertaking.
Hughes: I read that Kari Cantell, the Finn, who seemed to have the best cell source in the
seventies
Crea: Yes, human blood cells.
Hughes: Leukocytes?
Crea: Leukocytes, yes.
Hughes: made, with constant effort, a milligram a year.
Crea: From probably hundreds of thousands of liters. That tells you how difficult it was the
task of identifying the chemical structure of these molecules. I think that when that
became apparent, the race to identify the gene via messenger RNA and cDNA became an
incredible opportunity for biotech. Nobody could in the world reproduce what Professor
Cantell in Finland did, but now Genentech and other companies had the tool to attempt to
fish out the teeny, teeny amount of messenger RNA which is present in the cell with some
new and powerful tools called oligonucleotides synthetic DNA. And enzymes of
course, for the amplification.
Hughes: The hype was, and there was quite a bit of hype even before recombinant DNA got into
the picture, about how these interferon molecules were going to be the solution to cancer
and viral diseases.
80
Crea: Oh, viral diseases.
Hughes: Why when so little was known about interferon could one leap to that conclusion?
Crea: It was just a lot of interesting hypotheses based on cellular events. But nobody in the
world had enough material to test those hypotheses in real life in animals or even better
in humans. So it was like, because of what we see at the cellular base, the activity as an
anti-viral, that we imagine that if we had enough of this in our body, we could block the
viral activity. So that was really driving the interest. There was no clinical or pre-clinical
evidence that these molecules would work.
But among scientists, it was clear that these molecules eventually would play an
extremely important role in medicine based on studies and research at the cellular level.
That was enough to drive the interest of the pharmaceutical industry, and therefore the
interest of biotech companies like Genentech. But just to put things in perspective, we
didn t have any internal research on interferons. What we knew was just out of literature
or seminars, conferences. But we knew that we had the tools to be the first to fish out
extremely important information to be capable then to mass-produce these proteins in the
laboratory.
m
Crea: Fibroblast interferon, which was our first interferon project at Genentech started from
getting sequence information protein sequence information at a symposium. So that
was the extent of the information that was available with regard to the protein. A scientist
in his presentation at the symposium showed some slides with a partial sequence of these
proteins, which had been generated from a very teeny amount of interferon in Japan. The
scientists at Genentech literally by phone communicated back to our laboratory, and
from there we were able to build the genetic tools the DNA probes which then were
used to go and fish out the messenger RNA for a fibroblast.
Hughes: And you literally did that immediately after the phone call?
Crea: On a dime, essentially. Literally on the phone. The time that that slide was flashed on the
screen and the time of the telephone call, we were already up and running.
Hughes: The scientist who was listening to the presentation was Herbert Heyneker?
Crea: I believe it was Heyneker and David Goeddel.
Hughes: Amazing story.
Crea: In a way, it tells you a number of things. From a Genentech standpoint, it shows the
powerful machinery we had put in place to go from a small amount of information that
you can generate from the protein sequence two, three, four amino acids in a row to
the set of tools that you can put immediately in place to start a very unique and powerful
search for that teeny amount of messenger RNA.
81
Hughes: Right, and it may have been you who told me that Genentech s technological
preparedness to dive right in was not known. Otherwise, it s quite likely that the
presenting scientist would not have been quite so forthcoming. [Laughs]
Crea: Oh, absolutely. You are absolutely right. It was really outside any imagination that from
back east to California in a fraction of a minute you can trigger such a powerful set of
experiments out of flashing a slide. That was really the potential that we had built.
Obviously, I would never want to trivialize the work that was necessary to fish out the
gene, and sequence the gene, and clone I mean again, it was amazing how well oiled the
machine had become, to start even the most difficult challenge in biotech, but that was the
reality. We were in a unique position in the world to take advantage of a teeny piece of
information and trigger a series of events to really establish a leadership in the field,
which we did.
And we ended up being the first to isolate, clone, and sequence fibroblast interferon. That
led to a number of patents for the fibroblast interferon. The second time we tried for
leukocyte interferon we had the benefit of working with a powerhouse like Hoffmann-La
Roche. A molecular biology group at Hoffmann-La Roche led by Dr. Sidney Pestka
provided the information on the protein the small sequence required to design the DNA
probes.
Hughes: That relationship came after fibroblast interferon?
Crea: Yes, the leukocyte was later.
Hughes: Genentech did the fibroblast on its own without the association with Roche?
Crea: Correct. Then we made a deal with Roche only on leukocyte. Also, it s important to
understand that it wasn t just a simple go back to the laboratory and synthesize another
piece of DNA.
I think we very fortunate to have a library of dimers and trimers, which was built early on
at City of Hope for the insulin gene, a portion of which was transferred to Genentech.
Because of that library of dimers and trimers, we were able to assemble the DNA probes
in a unique fashion, as mixed probes to cover the redundancy of the genetic code. It s an
interesting exercise, but you understand that one amino acid doesn t necessarily tell you
that there s one codon. There are amino acids for which there are six codons. So we
wanted to select an area of the protein where there s the minimum amount of variability,
[tape interruption]
Hughes: Did anybody else have the ability to construct probes that would cover the redundancy?
Crea: No, there was nobody else in the world who could produce oligonucleotides to cover
quickly the redundancy, other than making individual oligonucleotides. We were already
ahead, and we were mixing trimers together so that you could generate two or four
oligonucleotides in the same pool. So imagine, out of a stretch of four amino acids, based
on the genetic code, you may have a number of different possible DNA sequences. By
using mixed trinucleotides to assemble the synthesized oligonucleotides, we were able to
cover all the possibilities in subgroups. So now you could work with a subgroup of four
82
different sequences to narrow down because the hybridization would occur only with
subset. That subset would narrow down the possibility. So it was a very clever way to
aft/*-* *t a at* tit A rr<af^ti/- -if* fXrm ot i r\n T^aolrirarrl
a
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engineer the genetic information backward.
Hughes: Is that immediately what you did when you had the phone call? You made these broad
probes?
Crea: Yes, exactly.
Hughes: Had you done that with other projects?
Crea: No, I think that was our first time. I think later on, because of the powerful amino acid
sequencing technology technology which was developed by companies like Applied
Biosystems for sequencing of peptides it became easier to access sequencing
information for proteins. But at the time we were working on interferons and other
molecules that technology wasn t available. So you needed a lot of material. Later on, it
became sufficient to have a fraction of a milligram. But that system eventually became
almost a method of choice to go from protein to oligonucleotide probes for the isolation
of messenger RNA.
Hughes: I believe when you first took on the interferon project, it wasn t clear that there was a
whole array of interferons. I mean people spoke of interferon.
Crea: Correct.
Hughes: Weren t all of the early biotech companies targeting interferon?
Crea: Correct. To some extent that was true for fibroblast interferon. I think alpha fibroblast
was the only species of fibroblast interferon, the predominant species. But for the
leukocyte, immediately the scientists at Genentech identified something like eight
different species. It was clear that they were two totally different situations.
Hughes: And all of that was unknown when you began?
Crea: It was unknown, yes.
Hughes: Then, so you were all of a sudden faced with not just one beta I think it became beta
interferon, right?
Crea: Yes, right.
Hughes: but many. So how does one choose which to develop? Or would it have been possible
to develop all of them up to a certain stage?
Crea: It was not so useful information to find out that there were multiple species because
obviously now the big dilemma was which one is more important. And still the answer
was not quite clear, because obviously each one might have its own function, its own
importance. For us, it wasn t just a matter of picking one; it was more a matter of
establishing an early patent position to block the competition from jumping on those
molecules which were discovered by Genentech.
83
Hughes: And did you have patent coverage for all eight?
Crea: Yes, I imagine yes all the sequences and even other sequences that were identified later
on. Yes, protein sequence is obviously very important in establishing intellectual
property. I m sure that Genentech did a good job in protecting that.
Hughes: But in the end, Genentech did pick and choose which interferon it actually worked on, did
it not?
Crea: Yes. Well, for instance, out of the information that came from the interferon research,
some of the biotech companies did select some molecules. Whether it was based on
proprietary, intellectual property, and biology, I think there was some early selection.
Interferon-alpha, for instance, became a therapeutic drug.
I remember Amgen came up with the idea of consensus interferon, which somehow was
the result of combining all the different variants in one molecule which represented the
entire community, [tape interruption] Yes, Amgen had a clever way to take a portion
from each natural protein to come up with what they thought was the most active
molecule. They called it consensus interferon.
Hughes: Did it work therapeutically?
Crea: Yes, it was a molecule which was developed therapeutically.
Hughes: That didn t interfere with the patents?
Crea: No, it s interesting because as you imagine, that was an obvious concept. But as I said
before, it becomes obvious after somebody
Hughes: Does it! [Laughs]
Crea: Does it for the first time. And obviously, nobody did it until Amgen produced that
consensus sequence, and they were able to cover that with patents and develop that
molecule.
Hughes: What kind of effect did that have on the commercial potential of what Genentech was
developing?
Crea: Well for one, it put the Amgen consensus interferon outside the patent umbrella. Very
often, that is the name of the game. You might have great molecules, but if somebody has
a patent you re not able to use them. Whether the consensus was an expedient to
circumvent the patent, or the result of science or scientific observation, it beats me. I
think it s most likely the first, because there was no way at that time to understand which
portion or which subunit might play a more important role. Again, it could be thought that
by having at your disposal many isoforms of the same protein, and having an assay,
you re capable of identifying a certain portion of the molecule which plays a more
important role, but I m not aware of any in the system.
Hughes: But the ultimate therapeutic function of these molecules was shifting over time because,
as we mentioned earlier, their role as spectacular cancer agents and anti-virals really
84
didn t pan out. So how can you select portions of molecules for function if you don t
know what the function is that you want?
Crea: You re absolutely right, and very often we rely on cell-based assays. In other words, you
rely upon the best assay that you have available to make some intelligent selections or
choices. I m sure that at that time, Amgen had cell-based assays to correlate the structure
of the different interferons with the activity on the cell.
Hughes: I see, so they did know.
Crea: So they knew, at least from a narrow angle that certain parts of certain proteins might be
important to that function. It s cutting and pasting, and I think that sometimes you re
lucky, and sometimes you re not. But it could have been also that this exercise of cutting
and pasting led to a more active molecule, where activity was essentially determined by a
cell assay. They probably decided that if it works better with a cell, ultimately it might
work better with human organs.
So you take the risk, and as you said, sometimes it works and sometimes it doesn t. But in
retrospect, the interferon research at Genentech is a great example of how the technology
wasn t just a tool to provide just the synthesis of protein, but it became itself a tool for
discovery. By applying biotechnology to a cellular system, scientists became capable of
making brand-new discoveries, which in turn, of course, fed the biotech industry and the
production of novel therapeutics.
Hughes: Well, I think we have to wind up, judging from all the phone calls you ve been getting.
You left Genentech because you wanted to use the technology that you d have a large
part in developing in more creative ways?
Crea: Absolutely, yes.
Hughes: Why couldn t that happen at Genentech?
Crea: It was becoming territorial. Interference. Genentech had grown from a dozen scientists
even less when I joined, we were only four or five to a few hundred, with a number of
departments, a number of senior people, a number of lead scientists.
Obviously the scientists started branching into a number of projects. For a laboratory like
mine, which had played an important role early on but was becoming more and more
service oriented, it was very difficult to become more than that without invading other
territories, without confronting other scientists and other ways of thinking. So it became
clear to me that the range of research that I could pursue was either in chemistry or
nothing at all. I wasn t really interested in developing the chemistry; I was more
interested in the end result of the beautiful recombinant DNA technology. So I was
becoming more and more frustrated by not controlling the outcome of the DNA software
I was building in my laboratory. I felt that maybe a small organization outside Genentech
where I could have my own people my own molecular biologists would give me a lot
more latitude.
85
Also, let s face it, I ve never been a large-company person. As Genentech started
becoming a large organization, I found myself more and more involved in meetings, not
only scientific, which I didn t mind, but also administrative and bureaucratic almost. A
lot of papers, office memos. I was spending a great deal of my time at my desk rather than
in my laboratory, and I was too young to play that role. I wanted to do something else.
Hughes: How did you approach Swanson with the fact that you were leaving? Or, when you
broached it to him, were you looking for some accommodation?
Crea: Well, I expressed my unhappiness and dissatisfaction with my role in different ways, I
guess. I waited until I had enough people in my department to be sure that I could leave
without disruption. After I hired some senior people to work with me on the chemistry, I
felt that with me leaving, Genentech could have gone on its own as before, getting all the
DNA they needed. It was at that time that I decided to prepare myself for an exit.
Ultimately, I went to Bob s office and I had a very open discussion with Bob, but I had
already crossed the bridge.
Hughes: You knew you were going?
Crea: Yes, I told him that there was no second-guessing; I was going to leave. I was going to
stay there until everything was ready for transition, but eventually I would leave shortly
after. Bob s reaction was of disappointment, but ultimately he looked at me and he said,
"I knew that you were going to do something like that." We shook hands and that was
inevitable. I mean I m sure Bob understood my desire to go out and be free to pursue
other interests. I promised I wasn t going to hire anybody from the company, and I
promised I was going to be available for the transition. Soon after, we agreed that I was
going to leave and pass the responsibility to the senior person I hired, and that was the
end.
Hughes: Did you ever have any regrets?
Crea: No, no regrets. Well, not from a career standpoint. From time to time I thought that
financially I could have been a lot better by staying with the company, but again probably
the price would have been too high. I didn t do too badly by leaving either.
Hughes: What were and are the restrictions placed on scientists who leave? How is the intellectual
property that you carry in your head controlled? Can it be?
Crea: There s no way you can stop people from using their brain, obviously, and every
employer in the world knows that. But in my case, perhaps because the way things had
evolved, it wasn t surprising that I decided to go out and start my own company. It
wasn t painful to Genentech in the extent that the DNA synthesis support was still there.
Nobody, including myself, had any idea what else was out there to be discovered with my
set of skills in DNA chemistry. If I had taken with me some new ideas developed during
my employment with the Company, then in that respect I would have had some
procedural obligation to Genentech. I was the very first senior person who left
Genentech by his own will, and that probably was a first. It was a surprise to Bob, but
Bob must have been very busy growing the company too.
86
Hughes: 1 98 1 -82 was a very busy period?
Crea: It was October 1981 . So the company was growing very rapidly, and of course Bob had
so many challenges and goals in his mind that my leaving probably wasn t a big deal. He
wrote a memo to the employees about me leaving. The major disappointment was to
leave my team, which I had built in two years. But it was the beginning of a new, exciting
experience.
Hughes: Did you keep in touch with your team to some extent after you left?
Crea: Well, physically, the company that I started, Creative Biomolecules, was in the Bay Area.
It was not far away from Genentech. We initially started in Brisbane by renting a couple
of laboratories and a couple offices from another company. We were in the South San
Francisco area, so it wasn t difficult to stumble into old colleagues. I remember I still kept
very good friendly relationships with some of the senior people, like Axel Ullrich, Peter
Seeburg.
##
Crea: There are new people, there are new challenges. That s the incredible environment in
which we live. We leave the old, and we are now getting immersed in the new and move
on. But my colleagues and some of my coworkers and I still spend some time together,
[tape interruption] Some of my early Genentech coworkers and I often go together for
lunch, remembering the good old times. [Laughter] In my years of being an entrepreneur,
I had the opportunity to meet a number of my former colleagues as well. The relationship
has always been good, but never based on working relationship, and no more scientific
collaborations. It was a clear cut between Genentech and my new organization.
Hughes: Was that a deliberate break on Genentech s part?
Crea: This is just a guess in my mind. Yes, I believe that Genentech wasn t interested in
working with a former scientist who left to start his own company. Again, it was very
early. I anticipated what happened later, two, three years later when there was a very
large number of scientists who left to pursue their own career as entrepreneurs. But being
the first to do it, that was probably perceived as a dangerous trend. Probably the
organization at Genentech didn t want to encourage other people to leave and start their
own company. In that respect I don t know for sure, but I believe that it was on purpose
not to collaborate with my new company.
Hughes: I see, and yet Genentech may hold the record for spawning more CEOs and other top
people of biotech companies than any other single company. But of course that was yet to
come. You were the first of the wave.
Crea: Yes, and I m not sure that it was ever a policy that Genentech encouraged internally.
Every time a key person leaves, it takes something out. So I believe that with Genentech
growing and becoming a pharmaceutical company and shifting its focus from the
research to development clinical development and business, it was easier to let some
bright scientist go out and try his own adventure in biotech. But early on, when the
company was heavily relying on the intellectual power of its scientists, it would have
been a disaster to let a large number of people go. So I m sure that I was perceived as a
87
rebel, maybe a little mad Italian, to leave the big family, the big cocoon, to go solo on his
own.
Hughes: Was it ever intimidating? You were leaving a fairly sure thing to go into something
whose future was unclear at best.
Crea: No, when I left I was thirty-three years old. So I was still very young to experience and go
through mistakes and learn out of your mistakes. I was lucky enough to start my
entrepreneurial career when I had some financial latitude from being involved with
Genentech early on. The courage comes from being young and being self-confident. I felt
that I wouldn t fail because I had too much of an important role early on at Genentech.
There were hundreds of new companies being formed which eventually would try to
reproduce things that Genentech had pioneered. And also, I believed I could eventually
help the industry to expedite that growth.
So I was confident that DNA service, which was my first business focus, would generate
a sufficient amount of business to support the new company. But obviously, I wasn t
thinking of doing the same thing I was doing at Genentech. Soon the business plan that
we put together for my new company, Creative Biomolecules, included the protein
engineering aspect, and the mixing and matching with DNA, which is called
mutagenesis, in a very precise and sophisticated fashion.
I started developing my own intellectual property. I filed for a number of patents, and I
proposed a number of interesting ideas, which ultimately helped people to design
different molecules and different proteins, and now we study the function/structure in a
more sophisticated fashion. By doing that, I had the opportunity to be involved not only
in molecular biology but also in protein biochemistry, immunology, cardiovascular, et
cetera
It was a beautiful learning experience by just doing it, and doing it with some original
approaches. So, no regrets. Great experiences and a great learning course. Every time I
did, I learned something different. Genentech remained this incredible scientific
experience and the beginning of my scientific and managerial career; I was at the right
place, with the right skills, with the right people, and I was capable of being part of an
extremely exciting story. [Laughs]
Hughes: Let me ask you one last question. Of which contribution thus far are you most proud?
Crea: Well, if I had just a single contribution in my mind, I would consider myself old
intellectually. I m always capable of getting excited about the next idea, or the idea I m
pursuing right now. I never thought about the biggest contribution. I think, honestly, that
everything I ve done in my career has had some degree of creativity and originality. I
think this a trend that has characterized my ventures in biotech and maybe even outside
biotech.
I enjoy technology and whenever there is a challenge, and I feel I have the tools to
participate in that challenge. I really get a kick out of it, and I was fortunate I was capable
of making some important contributions. The value of those contributions very often is
related to the timing in which the contribution happens, and the context in which it
88
happens, and the outside support that one might have to develop the positive outcome of
those contributions.
I have spent twenty-five years now in biotech, and looking back, some things I ve done
have been important, some less important. The things I m still doing today are going to be
even more important, [laughter]
Hughes: Good note to end on.
89
TAPE GUE)E--Roberto Crea
Interview 1: June 27, 2002
Tape 1, Side A 1
Tape 1, Side B 5
Tape 2, Side A 10
Tape 2, Side B 15
Interview 2: July 19, 2002
Tape 3, Side A 19
Tape 3, Side B 24
Tape 4, Side A 30
Tape 4, Side B not recorded
Interview 3: August 1, 2002
Tape 5, Side A 35
Tape 5, Side B 40
Tape 6, Side A 44
Tape 6, Side B 49
Interview 4: August 29, 2002
Tape 7, Side A 52
Tape 7, Side B 56
Tape 8, Side A 61
Tape 8, Side B 66
Interview 5: November 11, 2002
Tape 9, Side A 69
Tape 9, Side B 74
Tape 10, Side A 80
Tape 10, Side B 86
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91
APPENDIX
Curriculum Vitae 93
Bibliography 96
City of Hope Appointment Letter, May 1 6, 1 977 1 00
Genentech Appointment Letter, February 10, 1978 101
Letter from Crea to J. Van Boom, May 4, 1978 102
Genentech Performance Review, November 26, 1980 103
Letter from Bob Swanson announcing Crea s departure from Genentech, October 9, 1981 105
Letter from Tom Kiley announcing first Genentech patent, January 15, 1982 106
93
Professional Experience:
1998-present
CURRICULUM VITAE
DR. ROBERTO CREA
700 Occidental Avenue, San Mateo, CA.94402
650-343-7176 (Home) 650-732-8040 (Office)
President and Founder
Bioren, s.r.l. Metaponto, Italy
An Italian biotech company focused on the use of Plants for Medicine,
Environment and Energy applications.
1998-present
1 998-present
Past Experience
1994-1998
1991-1994
1982 to 1990
President and Founder
Caliscana, s.r.l. Capalbio, Italy
An agriculture company which produces unique natural products (Integrale
olive oil, Lavander and antioxidants for the Food, Cosmetic and Pharmaceutical
industry.
Chairman of the Board and Founder
Creagri, Inc. Hayward, CA. USA
A company which develops technology and products in the field of antioxidants
for the Food, Cosmetic and Pharmaceutical industry.
products
Vice President & Scientific Director
Neurex Corporation Menlo Park, CA. USA
A bio-medical company in the field of Neurosciences responsible for the discover
of Ziconotide, a pain killer for malignant and intractable pain.
In April 1998, Neurex was acquired by Elan Corp, Dublin (Ireland)
Founder, Chief Executive Officer and Chairman
Creagen, Inc. Cambridge, MA. USA
Biotech company for recombinant proteins with superior binding properties
and engineered catalytic activities for applications in human and animal
health care. Dr. Crea was responsible for the overall company business,
its scientific directions and technology development. Creagen was acquired
by Neurex Corporation in July 1994.
Founder, Scientific Director & Board Director
Creative BioMolecules, Inc. Hopkinton, MA. USA
Biotech company which develops healthcare products for soft and hard
tissue repair (bone repair).
94
1 978 to 1 982 Director of the DNA Chemistry Department
Genentech, Inc. South San Francisco, CA. U!
One of the initial four technical directors of the company.
Responsible for the creation and management of the company s DNA
chemistry department. Assembled and managed Genentech s DNA
team responsible for the gene synthesis for numerous therapeutic products
(Human Interferons, Human Growth Hormone, etc.)
Recipient of the company s first patent and co-author of several patents
and scientific articles. During this period, Dr. Crea published more than
thirty technical articles, including -the most cited article in Life Science
in 1979.
Recipient of the Rumbough Award for Scientific Contribution given by
the Juvenile Diabetes Foundation of America.
1977 to 1978 Scientist
City of Hope Medical Center/ Genentech, Inc. Duarte, CA. UJ
Responsible for the chemical synthesis of the genes for Human Insulin, the first
commercial product obtained by recombinant DNA.
Leading scientist during the synthesis of the genes for Human
Somatostatin gene and co-author of the first report of recombinant DNA
production of a mammalian hormone in bacteria.
This experiment marks the birth of modern biotechnology. " A scientific triumph of first orde
as defined by Prof. P. Handler, President of American Academy of Sciences before the U.S. S
Commission on Recombinant DNA in 1978.
Education :
1 974 to 1 976 Associate Professor - DNA Chemical Synthesis
Gorlaeus Laboratoria Leiden University The Netherlands
1973 to 1 974 EMBO (European Molecular Biology Organization)
Fellow - Enzymes and DNA Synthesis
Gorlaeus Laboratoria Leiden University The Netherlands
1 972 to 1 973 Academia dei Linceii, Italy,
Fellow - Biochemistry of Cartilage
University of Pavia Pavia, Italy
1973 to 1974 University of Pavia, Pavia, Italy
Specialty/Post Doctoral course in Biological Chemistry
1 970 to 1 972 University of Pavia. Pavia, Italy
Doctor Degree in Chemistry
Thesis Title: Localization of Glycosyl-transferases in Cartilage Cellular Sub-f-ractions
95
1 967 to 1 970 University of Messina, Italy . Messina, Italy
Corso in Chimica , anni 1-3
1 962- 1 967 Liceo Scientifico "Leonardo da Vinci" Reggio Calabria, Italy
Entrez-PubMed
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l;Zhou M. Demo SD. McClure TN, Crea R. Bitler CM. Related Articles, NEW
A novel splice variant of the cell death-promoting protein BAX.
JBiol Chem. 1998 May 8;273(19): 11930-6.
PMID: 9565621 [PubMed - indexed for MEDLINE]
Links
[~ -.Itakura K. Tadaaki H. Crea R. Riggs AD. Heyneker HL.
Bolivar F. Bover HW.
Related Articles, NEW Links
Expression in Escherichia coli of a chemically synthesized gene for the
hormone somatostatin. 1977.
Biotechnology. 1992;24:84-91. No abstract available.
PMID: 1358295 [PubMed - indexed for MEDLINE]
Related Articles, NEW Links
f~ .-i.Harley CB. Lawrie J. Betlach M. Crea R. Boyer HW.
Hedgpeth J.
Transcription initiation at the tet promoter and effect of mutations.
Nucleic Acids Res. 1988 Aug ll;16(15):7269-85.
PMID: 3045754 [PubMed - indexed for MEDLINE]
f~" j. Huston JS. Levinson D. Mudgett-Hunter M. Tai MS, Related Articles, NE
Novotny J. Margolies MN. Ridge RJ. Bruccoleri RE. Haber
E. Crea R. et al.
Protein engineering of antibody binding sites: recovery of specific
activity in an anti-digoxin single-chain Fv analogue produced in
Escherichia coli.
Proc Natl Acad Sci USA. 1988 Aug;85(16):5879-83.
PMID: 3045807 [PubMed - indexed for MEDLINE]
Links
r~ g.Alvarado-Urbina G. Chiarello R. Vilain G, Jurik F,
Christensen L. Carmona C. Fang L. Crea R.
Related Articles, NEW Links
Rapid automated synthesis via diisopropyl phosphoramidite in situ
activation. Chemical synthesis and cloning of a calmodulin gene.
Biochem Cell Biol. 1986 Jun;64(6):548-55.
PMID: 3017386 [PubMed - indexed for MEDLINE]
|~~ /r. Roberts DM. Crea R. Malecha M. Alvarado-Urbina G.
Chiarello RH. Watterson DM.
Related Articles, MEW Links
Chemical synthesis and expression of a calmodulin gene designed for
site-specific mutagenesis.
Biochemistry. 1985 Sep 10;24(19):5090-8.
PMID: 3000422 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm. nih.gov/entrez/query. fcgi?CMD=search&DB=PubMed
8/29/2002
Entrez-PubMed 97 Page 2 of 3
p y.Sharma OK, Engels J. Jager A. Crea R. van Boom J. Related Articles NEW Links
Goswami BB.
3 -O-methylated analogs of 2-5A as inhibitors of virus replication.
FEES Lett. 1983 Jul 25;158(2):298-300.
PMID: 6873284 [PubMed - indexed for MEDLINE]
FJ g.Quadrifoglio F. Manzini G. Dinkelspiel K. Crea R. Related Articles, NEW Links
Simultaneous stability of short alternating Z and B helices in synthetic
DNA concatamers.
Nucleic Acids Res. 1982 Jun 25;10(12):3759-68.
PMID: 71 1 1021 [PubMed - indexed for MEDLINE]
f~ p.Goswami BB. Crea R. Van Boom JR Sharma OK. Related Articles, NEW Links
2 -5 -Linked oligo(adenylic acid) and its analogs. A new class of
inhibitors of mRNA methylation.
J Biol Chem. 1982 Jun 25;257(12):6867-70.
PMID: 7085610 [PubMed - indexed for MEDLINE]
I"" iQ.Comb M. Herbert E. Crea R. Related Articles, NEW Links
Partial characterization of the mRNA that codes for enkephalins in
bovine adrenal medulla and human pheochromocytoma.
Proc Natl Acad Sci USA. 1982 Jan;79(2):360-4.
PMID: 6952189 [PubMed - indexed for MEDLINE]
[~ |j. Wetzel R. Kleid DG. Crea R. Heyneker HL. Yansura DG. Related Articles, NEW Links
Hirose T. Kraszewski A. Riggs AD. Itakura K. Goeddel
DV.
Expression in Escherichia coli of a chemically synthesized gene for a
"mini-C" analog of human proinsulin.
Gene. 1981 Dec;16(l-3):63-71.
PMID: 7044895 [PubMed - indexed for MEDLINE]
r |7.Ouadrifoglio F. Manzini G. Vasser M. Dinkelspiel K. Crea Related Articles NEW L i nks
&
Conformational stability of alternating d (CG) oligomers in high salt
solution.
Nucleic Acids Res. 1981 May 11;9(9):2195-206.
PMID: 6272229 [PubMed - indexed for MEDLINE]
I~ i g.Baglioni C. D Alessandro SB. Nilsen TW. den Hartog JA. Related Articles, NEW Links
Crea R. van Boom JH.
Analogs of (2 -5 )oligo(A). Endonuclease activation and inhibition of
protein synthesis in intact cells.
J Biol Chem. 1981 Apr 10;256(7):3253-7.
PMID: 6259158 [PubMed - indexed for MEDLINE]
F 14 : Messing J. Crea R. Seeburg PH. Related Articles, NEW Links
A system for shotgun DNA sequencing.
Nucleic Acids Res. 1981 Jan24;9(2):309-21.
PMID: 6259625 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=PubMed 8/29/2002
Entrez-PubMed 98 Page 3 of 3
[j | g . Wetzel R. Heyneker HL. Goeddel DV. Jhurani P. Shapiro Related Articles NEW Links
J. Crea R, Low TL. McClure JE. Thurman GB. Goldstein
AL.
Production of biologically active N alpha-desacetylthymosin alpha 1 in
Escherichia coli through expression of a chemically synthesized gene.
Biochemistry. 1980 Dec 23;19(26):6096-104.
PMID: 7008828 [PubMed - indexed for MEDLINE]
p i f Goeddel DV. Yelverton E. Ullrich A. Heyneker HL. Related Articles NEW Links
Miozzari G. Holmes W. Seeburg PH. Dull T. Mav L.
Stebbing N. Crea R. Maeda S. McCandliss R. Sloma A.
Tabor JM. Gross M. Familletti PC. Pestka S.
Human leukocyte interferon produced by E. coli is biologically active.
Nature. 1980 Oct2;287(5781):41 1-6.
PMID: 6159538 [PubMed - indexed for MEDLINE]
[^ 1 -.Goeddel DV. Shepard HM. Yelverton E. Leung D. Crea R. Related Articles NEW Links
Sloma A. Pestka S.
Synthesis of human fibroblast interferon by E. coli.
Nucleic Acids Res. 1980 Sep 25;8(18):4057-74.
PMID: 6159584 [PubMed - indexed for MEDLINE]
V ig. Crea R. Horn T. Related Articles, NEW Links
Synthesis of oligonucleotides on cellulose by a phosphotriester method.
Nucleic Acids Res. 1980 May 24;8(10):2331-48.
PMID: 7433092 [PubMed - indexed for MEDLINE]
l~~ 19;den Hartog JA. Wijnands RA. van Boom JH. Crea R. Related Articles, NEW ijnks
Chemical synthesis of an effective inhibitor of protein synthesis in
eukaryotic cells: pppA2 -5 A2 -5 A and some analogues.
Nucleic Acids Symp Ser. 1980;(7): 157-66. No abstract available.
PMID: 7255167 [PubMed - indexed for MEDLINE]
[~ 2Q T Riggs AD. Itakura K. Crea R. Hirose T. Kraszewski A. Related Articles NEW Links
Goeddel D. Kleid D. Yansura DG. Bolivar F. Hevneker
HL.
Synthesis, cloning, and expression of hormone genes in Escherichia coli.
Recent Prog Horm Res. 1980;36:261-76. Review. No abstract available.
PMID: 6997943 [PubMed - indexed for MEDLINE]
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P 21;Horn T. Vasser MP. Struble ME. Crea R. Related Articles, NEW Links
Synthesis of oligonucleotides on cellulose. Part II: Design and synthetic
strategy to the synthesis of 22 oligodeoxynucleotides coding for gastric
inhibitory polypeptide (GIP).
Nucleic Acids Symp Ser. 1980;(7):225-32.
PMID: 6265873 [PubMed - indexed for MEDLINE]
f~ ^T.Goeddel DV. Heyneker HL. Hozumi T. Arentzen R. Related Articles, NEW Links
Itakura K. Yansura DG. Ross MJ. Miozzari G. Crea R.
Seeburg PH.
Direct expression in Escherichia coli of a DNA sequence coding for
human growth hormone.
Nature. 1979 Oct 18;281(5732):544-8.
PMID: 386136 [PubMed - indexed for MEDLINE]
|~ 2->.Goeddel DV. Kleid DG. Bolivar F. Heyneker HL. Yansura R g | 3 ted Articles, NEW Links
DG. Crea R, Hirose T. Kraszewski A. Itakura K. Riggs
AD.
Expression in Escherichia coli of chemically synthesized genes for
human insulin.
Proc Natl Acad Sci USA. 1979 Jan;76(l): 106-10.
PMID: 85300 [PubMed - indexed for MEDLINE]
f~ 24;Crea R. Kraszewski A. Hirose T. Itakura K.
Chemical synthesis of genes for human insulin.
Proc Natl Acad Sci USA. 1978 Dec;75(12):5765-9.
PMID: 282602 [PubMed - indexed for MEDLINE]
Related Articles, NEW Links
f~ 3 g. Itakura K. Hirose T, Crea R. Riggs AD. Heyneker HL. Related Articles NEW Links
Bolivar F. BoverHW.
Expression in Escherichia coli of a chemically synthesized gene for the
hormone somatostatin.
Science. 1977 Dec 9;198(4321):1056-63.
PMID: 412251 [PubMed - indexed for MEDLINE]
r~ 26: s P eziale P- Pe Luca GC - Crea R - Ruggeri A, Balduini C. Related Articles, NEW Links
Subcellular localization of xylosyl-transferase in epiphysial -plate
cartilage.
Ital J Biochem. 1974 Sep-Oct;23(5):306-19. No abstract available.
PMID: 4452622 [PubMed - indexed for MEDLINE]
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CITY OF HOPE NATIONAL MEDICAL CENTER
1500 EAST DUARTE ROAD DUARTE. CALIFORNIA 91010 (213) 359-8111
OFFICE OF THE
EXECUTIVE MEDICAL DIRECTOR May 16, 1977
R. Crea, Ph.D.
Division of Biology
City of Hope Medical Center
Duarte, California 91010
Dear Dr. Crea:
It gives me great pleasure to appoint you as Research Associate
in the Division of Biology. This position becomes effective
May 2, 1977, with a salary of $12,000 per annum and is for a
period of one year. This is a full time position without major
consultant privileges. Individual consultantships and teach
ing assignments may be approved by the office of the Executive
Medical Director. You will be under the direction of Dr.
Itakura and responsible to Dr. Susumu Ohno, Chairman, Division
of Biology.
Yourg) sincerely,
Rachmiel Levine, M.D.
Executive Medical Director
RL:pd
cc: Dr. Itakura
Dr . Ohno
Administration
Personnel
101
GENENTECH
475 SANSOME STREET
FIFTEENTH FLOOR
SAN FRANCISCO. CA. 94111
415/396.3275
February 10, 1978
Dr. Roberto Crea
86 North Craig #6
Pasadena, CA 91107
Dear Roberto:
It is with great pleasure that I offer you the position of
Director of Organic Synthesis at Genentech. Herb Boyer and I are
in full agreement in our desire for you to join the Genentech team.
Your salary will be $30,000 per year. You will have an
opportunity to purchase 500 shares of Genentech common stock at
$3.00 per share. The company will lend you $1,000 to soften the
burden of the purchase. There is also a company-paid medical
plan.
I look forward to your favorable reply. You should plan to
start full time the first of September, but we should begin
arranging your visa and planning your laboratory immediately.
Personal regards,
M-
Robert A. Swanson
President
RAS/vl
Dr. Roberto Crea
Date
102
May 4, 1978
Professor J. Van Boom
Gorlaeus Laboratories
Rijksuniversitet of Leiden
The Netherlands
Dear Van Boom:
It was very nice to meet you in Birmingham last December; unfor
tunately I had no time to come to Leiden to visit you and your
family. My trip to Italy was very good and I enjoyed the Christ
mas atmosphere with my parents in Calabria. I also had a chance to
give some seminars and meet people at the University, but I had the
impression that there are very few possibilities to start some
research in our field in Italy.
On the other hand, the research in California is going very well,
and perspectives for the near future are very exciting. As I men
tioned to you in Birmingham, the synthesis of the insulin gene is
going very well and we expect to get its expression within a couple
of months. Many companies are now interested in the production of
biomedically valuable proteins by using this technology. Genentech
offered me the position of Director of Organic Synthesis in San
Francisco, starting next September. I am very happy to start my own
research in the oligonucleotides chemistry beside the improvements
in the synthesis of long oligonucleotides. As you can easily imagine
I am very busy setting up my lab and finding good people for my team.
I thought It was a good idea to offer one of these positions to some
people I have already been working with in Leiden, so I sent a
letter to Jack Den Hartog just in case he is looking for a job.
Naturally, the offer can be extended to any other person you wish to
recommend, in case Jack is not able to join me in San Francisco.
The next project probably will be the synthesis of the growth hormone
gene and we are planning to share the work between Itakura s lab and
mine.
I remind you that you promised to come and visit me in California.
You and your family will be very welcome. Thank you for your cooper
ation, and my best regards to you, Bep, and Stella.
Roberto Crea
RC:sp
103
PERFORMANCE REVIEW
GENERAL COMMENTS - OVERALL PERFORMANCE
Roberto is a respected and critical part of our scientific team.
In 1980 his team synthesized more DNA than had ever before been
synthesized by any group in the world. He will continue to be one
of the most important contributors to Genentech. His performance
is commendable.
PERFORMANCE -ACCOMPLISHMENTS
- Roberto has built a good nucleic acid synthesis team. He has
assembled the technical support to synthesize an unbelievable
amount of DNA fragments and genes.
- Roberto has done an excellent job of team building. The people
who work for him respect him and work hard for him. He has
also taken steps to integrate his team into the organization by
encouraging seminar attendance and inviting scientists from other
groups to talk about the use made of the DNA synthesized by his
team. (They should also be encouraged to talk about the results
of their experiements . )
- Roberto has accurately foreseen the advent of machine technology,
and is well along to perfecting one method of solid phase syn
thesis. He has chosen an excellent collaborator Waters Asso
ciates .
Roberto established a direct interaction with the Biology Depart
ment to take advantage of nucleic acid chemistry in making bio
logically active substances.
AREAS FOR PERFORMANCE IMPROVEMENT
Roberto needs to complement his own outstanding abilities in nu
cleic acid chemistry with outstanding organic chemists and other
nucleic acid viewpoints to keep Genentech s expertise at the
forefront. At least two top senior scientists need to join the
group as soon as possible. In order to remain the "best" in DNA
synthesis, Roberto should seek constructive criticism from his
to look at new technologies from the point of view of "what is
right with this and how can I incorporate it with my own good
ideas" .
PERFORMANCE REVIEW
Page I
104
AREAS FOR PERFORMANCE IMPROVEMENT ( Cont d . )
Roberto could make better use of Company consultants (especially
Whitesides) who might help him. A day visit to MIT to discuss
science in hte near future would be very worthwhile.
FOR THE FUTURE
Roberto may in the future want to concentrate on his own re
search with a small team, and to hire someone who would man
age his group. He should know that his position and status in
my eyes would not change and his compensation and reward for
his contributions to the Company would not be affected.
Date
fio\/.,
105
Distribution:
lienentech, Inc.
fcernal Correspondence
Cte October 9, 1981
1 All Employees
Bob Swanson
Sjject:
I am sorry to announce that Roberto Crea will be leaving Genentech on
October 14th.
Roberto was one of the early employees of the company. He helped synthesize
the genes for human insulin and was responsible for building our DNA
synthesis capability. We shall miss him, his garlic meatballs and his
pasta.
Roberto will be starting a specialty chemicals company that will initially
supply DNA linkers to Molecular Biology companies. Roberto will not
be competing with Genentech, and I hope that you will join me in wishing
him the best of luck.
Mark Vasser will continue as Manager of DNA synthesis and Chuck Hoyng
will be Acting Director of Nucleic Acid Research.
R.A.S.
106
3enentech, Inc.
(jt! P.>M>; i>.;it ii. ;:!-.. o. :i:icv.i!
oi!ih S.in ! ;. ir.i. 1 : -c.\ (. .\ > M/o
4i.^} ;)?:- loco
W\: . 1037: 7!-;.5
January 15, 1982
Roberto Crea, Ph.D.
Creative Biomolecules
430 Valley Drive
Brisbane, CA 94005
Dear Roberto:
I am enclosing a copy of the first United States patent
issued to Genentech which, as you will see, was the result
of "Crea-tivity" . As you know, the further application claim
ing the phosphorylating agent itself remains pending.
Congratulations !
Yours very truly,
Thomas D. Kiley
Vice President &
General Counsel
TDK : j cp
Enclosure
107
INDEX Roberto Crea
Alpha Laval: investment in Genentech, 41
Amgen
consensus interferon, 83-84
Noel Stebbing and, 64
Applied Biosystems, 82
Asilomar conference, 33
bacteria, expression of protein in, 20, 23, 29-30.
See also E. coli
Balduini, Cesare, 7-8
Beutler, Ernest, 45
biochemistry: Crea s early study of, 6-9
Biogen, 57
biotechnology, 32
applications of, 61
Genentech as pioneer in, 41, 61-66
and human insulin, 44
and intellectual property, 50-5 1
and scientist/entrepreneur hybrid, 47-48,
86-87
Bolivar, Francisco, 23
Boyer,Herb, 16,20,33,61
and Genentech executive board, 75-76
as founding scientist of Genentech, 41
and Hoffmann-La Roche, 40
"hybrid" position of, 46-47
and insulin project, 30, 46-47, 49
and recruitment, 58
and somatostatin, 23-24, 25
Burgers, Peter, 12-13, 17
Byers, Brook, 35
California Institute of Technology [Caltech]: and
somatostatin, 30-31
Campagnari, Francesco, 9, 10-11, 15, 16
research plan of, 12, 13
Cantell, Kari, 79
cartilage: Crea s early research on, 7-9
Castellani, Alessandro, 7-10
Cetus: as Genentech competitor, 56-57
chemistry: Crea s early study of, 5-10
City of Hope, 15
collaboration with Genentech, 20, 21, 23-
26, 36, 44-47, 52-53
Crea s arrival at, 17-18, 19-20
Crea s departure from, 35, 37
gene synthesis at, 13, 17, 20
HPLC at, 19-20, 21
and human growth hormone, 52-54
and human insulin, 25-27, 28-30, 44-47
patents, 49-51
publication policy, 59
recruitment of Crea, 16-17
solid-phase nucleic acid synthesis at, 55-
56
and somatostatin, 23-25, 30-31
cloning: of bovine growth hormone, 36. See also
DNA; gene synthesis; insulin;
somatostatin
Ciba-Geigy, 66
Crea, Francesco (father), 1, 2, 4, 5
Crea, Palma (sister), 2, 5
Creative Biomolecules: founding of, 86, 87
Cuzzocrea, Giovanni, 6-7
De Boer, Herman, 65
de Roy, Jan, 12
diabetes: and insulin supply, 39
Diamond v. Chakrabarty, 5 1
dimers and trimers, library of, 22-23, 26, 81
DNA
Crea s early interest in, 9
recombinant, 20, 23-24, 25, 33, 47, 48-49,
50, 73-74, 78, 84
replication, 9
DNA chemistry, 10-11, 12-14, 15, 22, 32
at City of Hope, 17, 20-34
at Genentech, 35, 52-56, 71-74
in Holland, 10-11, 12-14, 15, 22, 32
and somatostatin, 25
DNA synthesis, 42, 52, 64-66, 71-74, 79, 85
at City of Hope, 13, 17, 21-24, 31
expression, 53, 54
and human growth hormone, 53-54
and human insulin, 45-46
purification, 52
solid-phase, 55-56, 65
DNA synthesizer, 64-66
E. coli
expression of growth hormone in 36, 54
expression of insulin in, 29-30, 37-38, 46,
48-49
expression of proinsulin in, 77, 78-79
expression of somatostatin in, 23
and sequencing system, 65
Eli Lilly
and proinsulin, 77-78
108
relationship with Genentech, 39-40, 52, 61
Euratom, 10
European Commission, 1 1
European Community: Crea s grant from, 10, 11,
13,14
European Molecular Biology Organization
[EMBO]: Crea s grant from, 11, 13, 14
Farley, Peter, 57
FDA, 33, 39, 78
fibroblast interferon. See interferon, human
foot and mouth disease, 40
Fox, Shirlee, 34
gastrointestinal peptide [GIF], 73
Genentech, 15
Boyer s role in, 46-48
and Cetus, 56-57
and Chakrabarty decision, 5 1
collaboration with City of Hope, 20, 21-
34, 36, 52-56
collaboration with UCSF, 52-54
competition among scientists, 55, 65-66
construction of labs, 35-36
consulting scientists, 42-43
Crea s arrival at, 35-36
Crea s departure from, 84-87
Crea s recruitment by, 16-17, 20-21, 31
departments in, 66
early atmosphere of, 52-56
and Eli Lilly, 39-40, 52, 60, 62
executive board, 41-42, 75-76
as FIPCO, 40, 60, 62, 66
growth, 64-65, 75
hiring problems, 43-44
and Hoffmann-La Roche, 52
IPO, 50-51,60-61,66-68
and Lubrizol, 41, 60-61, 66
patents, 22, 48-51, 59, 81, 83-84
pioneer in biotechnology, 41, 61-66
publication policy, 58-59
recruitment, 58
and scientist/entrepreneur hybrid, 47-48,
86-87
and scientist managers, 40
shares in, 31-32, 66, 67
and Stanford Research Institute [SRI], 63-
64
Genentech research projects
bovine growth hormone, 62
gastrointestinal peptide [GIP], 73
human growth hormone, 36-37, 52-54, 62,
78
human insulin project, 25-27, 28-30, 36-
39, 44-49, 53, 72-74
human interferon, 40, 57-58, 74, 78, 79-80
proinsulin, 72, 76-78
somatostatin, 23-25, 30-31, 49-50
thymosin, 69-70, 71, 74
gene synthesis, 20, 30. See also DNA synthesis;
and individual research projects
Gilbert, Wally, 57
Goeddel, David, 31-32, 35, 66
and fibroblast interferon, 80
and human growth hormone, 36, 52
and human insulin, 37, 49
Goodman, Howard, 53
Gorlaeus Laboratory (Leiden), 11-12, 13
growth hormone, bovine, 36, 62
growth hormone, human, 36-37, 52-54, 62, 78
success of, 40
Handler, Phil, 25
Heidelberg, University of: relation with Biogen, 57
Heyneker, Herbert, 13, 66
and fibroblast interferon, 80
and human insulin, 30, 49
and recruitment of Crea, 16-17
and somatostatin, 23
Hirose, Tadaaki, 19-20, 24
and human insulin, 45
Hoffmann-La Roche, 52, 60
and interferon project, 40, 81
Holland, 8
study of DNA chemistry in, 10-11, 12-14,
15, 22, 32, 55
Horn, Thomas, 55
HPLC [high performance liquid chromatographer],
37-38, 65
at City of Hope, 19-20, 23, 27
Crea s experience with, 20-21
in Holland, 15
and insulin, 29, 37
insulin, bovine, 39
insulin, human, 53, 66
expression of, 28-30, 36-39, 48-49, 54, 56
patent, 48-49
press conference announcing, 44-45
published papers, 45-46
109
synthesis of; 25-27, 36-39, 72
interferon, human, 74, 78, 79-80
beta, 82
fibroblast, 57-58, 80-84
and Hoffinann-La Roche, 40
patents, 81, 83
Itakura, Keiichi, 28, 31, 34, 36
Crea s first meeting with, 19-20
and Crea s move to Genentech, 35
group of, 21-34
and human growth hormone, 36, 52, 53
and human insulin, 25-26, 30, 36, 44, 45,
46
and recruitment of Crea, 16-17, 21
and somatostatin, 23-25
and triester approach (DNA synthesis), 22-
23
Italy
and Crea s Italian heritage, 15-16
Ministry of Scientific Affairs, 7
study of DNA in, 9, 16
university system in, 6, 7, 14-15
Jhurani, Parash, 36
Johnson, Irving, 39
Khorana, Gobind, 22, 56
Kiley, Thomas, 41, 51
legal review of publications, 59
King, Eli, 34
King s College London, 12
Kleid, Dennis, 31-32, 35, 66
and human growth hormone, 36, 52
and human insulin, 45
Kleiner, Eugene, 33
Komberg, Arthur, 9
Kraszewski, Adam, 27-28
Leiden, University of, 14-17, 22, 32
Letsinger, Robert, 22
Levine, Rachmiel, 45
Linceii, Academy of, 10
Lubrizol: investment in Genentech, 41, 60-61
Martin, David, 66
Massachusetts Institute of Technology [MTT]:
connection to Genentech, 41, 42
Messina, University of, 5-7, 8
Middleton, Fred, 67
Milea, Bruno (grandiather), 1
Milea, Caterina (grandmother), 1
Milea, Giuseppina (mother), 1, 2, 4, 5
mini-proinsuhn, 65. See also insulin, human;
promsuhn
Miozzari, Giuseppi
and human growth hormone, 36, 52
scientific director at Genentech, 66, 72
molecular biology
Crea s interest in, 9-10, 71
and insulin project, 37
Murfin,Don,41
Narang, Saran, 22, 56
Nature, 59, 68
Nffl.33
oligonucleotides
and human growth hormone, 36
and insulin, 25-27
purification of, 20-21, 22, 23, 26-27, 36-37
synthesis of, 20, 26, 31
Ono, Susumo, 30
Perkins, Thomas, 31, 33-34, 41
and Genentech executive board, 75
Pestka, Sidney, 81
phosphotriester approach, 22-23. See also Itakura,
Keiichi
Plum Island, 40
Proceedings of the National Academy of Sciences
[PNAS], 45-46, 59
expression of, 72, 76-78
mnn-proinsuhn, 72
applications in biotechnology, limitations
of, 61-62
-based drugs, 40
engineering, 28
expression of, 20, 23, 36, 46, 53, 54, 56,
77, 78-79
and mutagenesis, 65
purification of, 40
sequence, patents for, 83
synthesis of, 36-37, 47, 48-49, 53, 54, 71-
74, 75, 78-79
recombinant DNA. See DNA, recombinant
Riggs,Art
and human insulin, 29-30, 44, 45, 46
protein
110
and somatostatin, 23-24
Reese, Colin, 11-12,22
RNA (messenger), 9, 12, 65, 79, 80
Rosch, Arthur, 16-17
Rosch, Thrus, 16
San Francisco Chronicle: and Genentech IPO, 67-
68
Scheller, Richard, 31
Science, 59, 68
Securities and Exchange Commission [SEC], 68
Seeburg, Peter, 58, 65, 86
and human growth hormone, 36, 52, 53-54
sequencing: and. coll., 65
Serono: and human growth hormone, 62
Shine, John, 58
Silvius Laboratory (Leiden), 13
solid-phase synthesis of nucleic acids, 55-56
somatostatin, 49-50, 72
expression of, 28, 38
purification of, 29-30
synthesis of, 20, 23-25
Stanford Research Institute [SRI]: collaboration
with Genentech, 63-64
Stebbing, Noel, 63-64, 75
Swanson, Robert, 20, 28, 31, 33, 40, 61
and City of Hope, 53
and Crea s move to Genentech, 35
and Crea s departure, 85
Crea s personal relations with, 35, 42, 43
and executive board, 41-42, 75-76
and Genentech as FIPCO, 40
and human insulin project, 25-26, 45, 49
and IPO, 66
and MIT, 41, 42
negotiations with Eli Lilly, 39, 60
recruitment efforts, 58
and recruitment of Crea, 16-17, 21,31
relations with scientists, 41-43, 52, 55, 56
review of Crea, 42
and somatostatin, 23-24, 25
vision, 48, 62
thymosin, 69-70, 71,74
triester approach. See phosphotriester approach
Ullrich, Axel, 58, 86
United States Army: and foot and mouth vaccine,
40
United States Supreme Court: and the Chakrabarty
decision, 5 1
University of California, San Francisco [UCSF],48
Boyer s group at, 20, 30
and human insulin, 46-47, 49
relations with Genentech, 52-54
and somatostatin, 25, 30, 49-50
Vale, Wiley: and somatostatin, 24
Van Boom, Jacques, 21, 22
dealings with City of Hope/Genentech, 16-
17, 20-21
work on DNA synthesis, 10, 11-12, 13-14,
15
Van Boom, Lisbeth, 15
Van Boom, Stella, 15
Van Deursen, Peter, 12, 13
Waters Associates, 65
Whitesides, George M.: consultant for Genentech,
76
Yale University, 44
Sally Smith Hughes is a historian of science at ROHO whose research focuses on the recent
history of biomedicine. She began work in oral history at the Bancroft Library in 1978 and joined
ROHO in 1980. She has conducted interviews for over 100 oral histories, whose subjects range
from the AIDS epidemic to medical physics. Her focus for the past decade has been on the
biotechnology industry in northern California. She is the author of The Virus: A History of the
Concept and an article in Isis, the journal of the History of Science Society, on the
commercialization of molecular biology.
,
At 55
Open Library
